Materiały źródłowe

• #1 Pathogenesis of Diabetic Nephropathy – Chronic Kidney Disease and Type 2 Diabetes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571720/

  Our understanding of the natural history of diabetic nephropathy has emerged largely from patients with type 1 diabetes. However, histological manifestations among those with type 2 diabetes are similar. Both the clinical manifestations and the histological appearances of kidney disease associated with diabetes have been well characterized. The pathogenesis, however, is less well understood, and there are gaps in our understanding of how various causal factors relate to the histological manifestations of diabetes; in part, this is because of a paucity of kidney biopsies and longitudinal data. Here, we will focus on the pathogenesis, summarizing our current understanding of the histological and clinical correlates and pointing out remaining controversies in the context of pathogenesis. […] The pathogenesis of diabetic nephropathy is initiated and maintained by four causal factors, which can be classified broadly into metabolic, hemodynamic, growth, and proinflammatory or profibrotic factors. Although there is both a substantial overlap among these factors and variability in their relative contribution among individuals and over time, for ease of discussion, we will describe the pathogenesis as if each factor played an isolated role. These pathogenetic factors produce lesions in various kidney compartments: glomeruli, tubuli, interstitium, and vasculature. A complex series of molecules, receptors, enzymes, and transcription factors participate in the process that drives the earliest stages of kidney disease to an enlarged kidney with hypertrophy, expanded extracellular matrix (ECM), glomerulosclerosis, vascular hyalinosis, interstitial fibrosis and tubular atrophy, and loss of function culminating in end-stage renal disease (ESRD).

• #2 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. […] The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. […] The development and progression of DKD are believed to stem from the complex interplay of metabolic, hemodynamic, inflammatory, and fibrotic factors, which are frequently disrupted in DM. […] Dysfunction in these factors may be interlinked, influencing gene regulation, activating transcription factors, and affecting molecular pathways. […] These interactions lead to functional and structural changes culminating in the clinical manifestations of DKD, characterized by escalating albuminuria and declining renal function.

• #3 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries, including the United States. As a microvascular complication, it affects individuals with both type 1 and type 2 diabetes. The primary pathological features of diabetic kidney disease (DKD) include glomerular hypertrophy, glomerular basement membrane thickening, effacement of podocyte foot processes, and mesangial matrix expansion. […] Hyperglycemia triggers the production of reactive oxygen species and activates several molecular pathways. These interconnected pathways drive the onset and progression of diabetic nephropathy by promoting inflammation, fibrosis, endothelial dysfunction, and podocyte damage. Gaining insight into these mechanisms can lead to the development of novel therapeutic strategies.

• #4 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  Diabetic kidney disease (DKD) has been an immense burden on the healthcare system, and is the leading cause of end stage kidney disease worldwide. DKD involves various intersecting pathways that lead to progressive kidney damage. […] Due to its versatile pathogenesis, DKD has been a formidable adversary. […] The end result of uncontrolled hyperglycaemia in the kidney is nephron death. This manifests in the form of glomerulosclerosis, interstitial fibrosis, and tubular atrophy, but there are a lot of milestones and instigators along the way. […] Hyperglycaemia leads to hyperfiltration, which is followed by metabolic, hormonal, haemodynamic, inflammatory and epigenetic changes. Oxidative stress and hypoxia play a vital role. All these precipitate to podocyte injury, mitochondrial distress, tissue death, glomerulosclerosis, and interstitial fibrosis.

• #5 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

• #6 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  Endothelial cell damage is one of the earliest pathological changes in diabetic nephropathy. This damage generates reactive oxygen species, which are major contributors to the progression of diabetic nephropathy. […] Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. […] The polyol pathway contributes to diabetic nephropathy through the accumulation of fructose and sorbitol, glucose byproducts that increase osmotic pressure, leading to edema and cell membrane rupture. […] Genetics is crucial for the development of diabetic nephropathy, with both genetic and environmental factors contributing to its onset. […] Patients with T2D may present with albuminuria at the time of diabetes diagnosis, whereas diabetic nephropathy typically develops 15 to 20 years after the onset of T1D.

• #7 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  While conventional approaches like optimal blood pressure control through renin–angiotensin–aldosterone system (RAAS) blockade and glycemic control have demonstrated efficacy in slowing down the progression of DKD, they do not halt or reverse the condition. […] The PKC pathway is associated with the advancement of DKD by narrowing small blood vessels in the kidney and thus affecting the function of glomeruli. […] In DKD, expansion of the glomerular basement membrane (GBM) and the accumulation of ECM are notable features. […] Transforming growth factor β1 (TGF-β1) plays a significant role in the accumulation of GBM and ECM in DKD. […] The activation of PKC overexpression is implicated in ECM accumulation, primarily arising from mesangial cells. […] The role of inflammation in the progression of DKD is significant, with various inflammatory cytokines contributing to renal injury.

• #8

  https://step1.medbullets.com/evidence/11460589

  Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. […] There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. […] The pathogenesis of diabetic nephropathy is not clarified completely yet.

• #9 Diabetic nephropathy – Wikipedia

  https://en.wikipedia.org/wiki/Diabetic_nephropathy

  Metabolic factors include the formation of advanced glycation end-products (AGEs), which have a central role in the pathophysiology of many of the complications of diabetes mellitus, including cardiovascular complications. […] These glycation products accumulate on the proteins of vessel wall collagen, forming an irreversible complex of cross-linked AGEs. An important way AGEs exert their effect is through a receptor-mediated mechanism, most importantly by the receptor for advanced glycation end products (RAGE). […] Bindings of AGEs to RAGE receptors enhances production of cytosolic Reactive Oxygen Species (ROS) as well as stimulates intracellular molecules such as Protein Kinase C (PKC), NF-B and the activation of growth factors TGF-B and vascular endothelial growth factor (VEGF). […] These factors, along with the hemodynamic changes that occur, lead to podocyte injury, oxidative stress, inflammation and fibrosis.

• #10 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Diabetes-mediated chronic hyperglycaemia, which causes an increase in the osmolarity within glomerular capillaries leads to an increase in glomerular pressure and dilation of afferent arterioles, causing glomerular hyperfiltration, resulting in increased glomerular filtration rate. These haemodynamic alterations also initiate and activate several vasoactive systems within the kidneys that further contribute to the progression of DKD. These include the activation of the renin–angiotensin–aldosterone system (RAAS), protein kinase C (PKC), polyol and advanced glycation end product (AGE) dependent pathways as well as the more recently explored pro-oxidant enzyme NADPH oxidases. In particular, the increase in angiotensin II which is a key effector hormone of the RAAS stimulates the vasoconstriction of the efferent arteriole, further increasing the intraglomerular pressure and subsequent hyperfiltration. The resulting increase in glomerular filtration rate and glomerular capillary pressure leads to glomerular and tubular injury.

• #11 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Oxidative stress plays a critical role in the initiation and progression of DKD. Chronic hyperglycaemia induces oxidative stress via enhanced reactive oxygen species (ROS) production and diminished antioxidant defence in DKD. Chronic hyperglycaemia disrupts the homeostatic balance between pro-oxidant and antioxidant pathways whereby there is an upregulation of pro-oxidant enzyme-derived ROS formation and an accompanied reduction in antioxidants, causing oxidative stress within the kidneys. Recent accumulating evidence demonstrates the overproduction of intrarenal ROS in diabetes and subsequent haemodynamic alterations and metabolic changes as a key mediator and a common denominator of the pathways leading to disrupted renal function and pathological structural changes in DKD. […] In DKD, inflammation plays an important role. It is driven by multiple pathways including oxidative stress, activation of transcription pathways such as JAK/STAT and transcription factors including nuclear factor κB (NF-κB) and the activation of pro-inflammatory cytokines.

• #12

  https://step1.medbullets.com/evidence/11460589

  Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. […] There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. […] The pathogenesis of diabetic nephropathy is not clarified completely yet.

• #13 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  The 3 main pathological lesions of diabetic nephropathy include diffuse mesangial cell expansion, GBM thickening, and arteriolar hyalinization. […] Hyperfiltration is one of the earliest pathological changes observed in diabetic nephropathy, involving both the glomeruli and renal tubules. […] Abnormal renal pathology is evident even before the onset of microalbuminuria. Characteristic lesions observed on light microscopy include thickened glomerular and tubular basement membranes, diffuse mesangial expansion, and arteriolar hyalinosis. […] A longer duration of diabetes mellitus, poor glycemic control, and uncontrolled hypertension are significant risk factors for developing diabetic nephropathy. […] Diabetic nephropathy is associated with high morbidity and mortality. Microalbuminuria is an independent risk factor for cardiovascular mortality, and the majority of patients ultimately die from ESRD.

• #14 Diabetic nephropathy – Wikipedia

  https://en.wikipedia.org/wiki/Diabetic_nephropathy

  Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. […] Pathophysiologic abnormalities in diabetic nephropathy usually begin with long-standing poorly controlled blood glucose levels. This is followed by multiple changes in the filtration units of the kidneys, the nephrons. […] Initially, there is constriction of the efferent arterioles and dilation of afferent arterioles, with resulting glomerular capillary hypertension and hyperfiltration particularly as nephrons become obsolescent and the adaption of hyperfiltration paradoxically causes further shear stress related damage to the delicate glomerular capillaries, further proteinuria, rising blood pressure and a vicious circle of additional nephron damage and decline in overall renal function.

• #15 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  Hyperglycaemia initiates its effects on the kidney by disturbing the osmotic forces. […] Hyperglycaemia and SGLT2-assisted decreased distal sodium delivery leads to activation of RAAS, producing efferent arteriolar vasoconstriction and afferent vasodilation, and amplifying intraglomerular hypertension. […] Diabetes is associated with dysregulation of multiple metabolic pathways. […] Inflammation plays a vital role in the pathogenesis of DKD. […] The complement system activation has a huge impact on DKD progression. […] Hyperglycaemia and its effects cause DNA damage, and display effects of ageing in patients with diabetes by causing chromosomal telomere shortening, resulting in proteinuria and DKD progression. […] The kidneys in a diabetic environment undergo many changes, from initial renal enlargement to vasoconstriction, endothelial and tubular cell injury, to eventual renal fibrosis.

• #16 Diabetic nephropathy (kidney disease) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diabetic-nephropathy/symptoms-causes/syc-20354556

  Diabetic nephropathy is a serious complication of type 1 diabetes and type 2 diabetes. It’s also called diabetic kidney disease. In the United States, about 1 in 3 people living with diabetes have diabetic nephropathy. […] Diabetic nephropathy happens when diabetes damages blood vessels and other cells in the kidneys. […] Over time, diabetes that isn’t well controlled can damage blood vessels in the kidneys that filter waste from the blood. This can lead to kidney damage and cause high blood pressure. […] The kidneys have millions of tiny blood vessel clusters called glomeruli. Glomeruli filter waste from the blood. Damage to these blood vessels can lead to diabetic nephropathy. The damage can keep the kidneys from working as they should and lead to kidney failure. […] Diabetic nephropathy is a common complication of type 1 and type 2 diabetes. […] High blood pressure can cause more kidney damage by raising the pressure in the filtering system of the kidneys.

• #17 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

• #18 Pathogenesis of diabetic kidney disease

  https://www.degruyterbrill.com/document/doi/10.2478/dine-2021-0004/html?srsltid=AfmBOooRUbi93sSokG57HWhgqkD-kaBxSj6pY0QJwcfZEX_3eymeHA-x

  Inflammatory processes and immune cells are involved in the development and progression of DN. Glomerular and interstitial infiltration by monocytes/macrophages and activated T lymphocytes as well as heightened Nlrp-3 inflammasome activation are observed both in human and experimental DN. […] Widening of the glomerular basement membrane (GBM) is associated with accumulation of type IV collagen and a net reduction in negatively charged heparin sulfate proteoglycan. The expression of one permeability-controlling protein, nephrin, is abnormally low in DN. […] Although glomerulosclerosis is a cardinal feature of DN, tubulointerstitial injury ultimately determines the rate of attrition of renal function. […] In patients with DN, Ang II has many nonhemodynamic effects and mediates cell proliferation, hypertrophy, ECM expansion, and cytokine (TGF-, VEGF) synthesis. […] Increasing evidence shows epigenetic mechanisms, involving chromatin histone modifications, DNA methylation, and non-coding RNAs contribute to the development of DN. […] Lipotoxicity is another pathway that is increasingly implicated in DN.

• #19 Diabetes and others

  https://www.kidneypathology.com/English_version/Diabetes_and_others.html

  Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycation of matrix proteins. Second, thickening of the glomerular basement membrane (GBM) occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). […] The progression of the initial changes in DN depends much on the control of glycemia and other risk factors, so, the time interval between initial changes and terminal renal damage is highly variable. DN can appear in renal allografts as recurrence or as de novo disease. DN is developed more quickly in the transplanted kidney that in native kidneys: in average six post-transplantation years.

• #20 Diabetes and others

  https://www.kidneypathology.com/English_version/Diabetes_and_others.html

  Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycation of matrix proteins. Second, thickening of the glomerular basement membrane (GBM) occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). […] The progression of the initial changes in DN depends much on the control of glycemia and other risk factors, so, the time interval between initial changes and terminal renal damage is highly variable. DN can appear in renal allografts as recurrence or as de novo disease. DN is developed more quickly in the transplanted kidney that in native kidneys: in average six post-transplantation years.

• #21 Diabetes and others

  https://www.kidneypathology.com/English_version/Diabetes_and_others.html

  In DN the glomeruli present increase (sclerosis) of the mesangial intercapillary matrix, with progressive increase of the thickening of capillary walls and later evolution to global glomerulosclerosis. […] If hyaline arteriolosclerosis is very prominent in young patients, it must alert us on the possibility of DN. Arteriolar lesions may involve any arteriole; if we demonstrated arteriolar hyalinosis in both glomerular arterioles (afferent and efferent) it is virtually pathognomonic of DN.

• #22 Pathogenesis of Diabetic Nephropathy – Chronic Kidney Disease and Type 2 Diabetes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571720/

  Inflammation and fibrosis are important causes of diabetic nephropathy. Whether this is causal or in response to injury remains a matter of debate. However, there is a strong relation between the degree of infiltration of macrophages and subsequent occurrence of tubular interstitial fibrosis and progression of diabetic kidney disease. […] The pathogenesis of diabetic nephropathy involves metabolic, hemodynamic, growth, and inflammatory and fibrotic factors. The relative contributions of these factors vary among patients, over time, and even in different compartments of the kidney, and genetic and environmental factors can modify the appearance of the kidney lesions. AKI plays an important role in the progression of kidney disease in patients with diabetes. MR activation, particularly in the myeloid cells, may be important in mediating inflammation and fibrosis in CKD and after AKI in individuals with type 2 diabetes, and MR antagonist therapy may be protective.

• #23 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  Hyperglycaemia initiates its effects on the kidney by disturbing the osmotic forces. […] Hyperglycaemia and SGLT2-assisted decreased distal sodium delivery leads to activation of RAAS, producing efferent arteriolar vasoconstriction and afferent vasodilation, and amplifying intraglomerular hypertension. […] Diabetes is associated with dysregulation of multiple metabolic pathways. […] Inflammation plays a vital role in the pathogenesis of DKD. […] The complement system activation has a huge impact on DKD progression. […] Hyperglycaemia and its effects cause DNA damage, and display effects of ageing in patients with diabetes by causing chromosomal telomere shortening, resulting in proteinuria and DKD progression. […] The kidneys in a diabetic environment undergo many changes, from initial renal enlargement to vasoconstriction, endothelial and tubular cell injury, to eventual renal fibrosis.

• #24 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  While conventional approaches like optimal blood pressure control through renin–angiotensin–aldosterone system (RAAS) blockade and glycemic control have demonstrated efficacy in slowing down the progression of DKD, they do not halt or reverse the condition. […] The PKC pathway is associated with the advancement of DKD by narrowing small blood vessels in the kidney and thus affecting the function of glomeruli. […] In DKD, expansion of the glomerular basement membrane (GBM) and the accumulation of ECM are notable features. […] Transforming growth factor β1 (TGF-β1) plays a significant role in the accumulation of GBM and ECM in DKD. […] The activation of PKC overexpression is implicated in ECM accumulation, primarily arising from mesangial cells. […] The role of inflammation in the progression of DKD is significant, with various inflammatory cytokines contributing to renal injury.

• #25 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The increase in AGEs has been directly associated with an elevated expression of NLRP3-related proteins, which have been proposed as mediators of CKD, potentially activating mesangial cells. […] In summary, DKD involves multiple intertwined pathways, with inflammation also playing a pivotal role in its development. […] The major signaling pathways implicated in renal fibrosis encompass the TGF-β, MAPK, Wnt/β-catenin, PI3K/AKT, JAK/STAT, and Notch pathways. […] It is widely recognized that TGF-β stands as the most significant profibrotic cytokine, serving as a primary driver of renal fibrosis in DKD. […] The success of inhibiting TGF-β1 signaling in animal studies has prompted clinical investigations in DKD. […] The Wnt canonical and non-canonical pathways have been identified as another key player in the progression of DKD.

• #26 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  Hyperglycaemia initiates its effects on the kidney by disturbing the osmotic forces. […] Hyperglycaemia and SGLT2-assisted decreased distal sodium delivery leads to activation of RAAS, producing efferent arteriolar vasoconstriction and afferent vasodilation, and amplifying intraglomerular hypertension. […] Diabetes is associated with dysregulation of multiple metabolic pathways. […] Inflammation plays a vital role in the pathogenesis of DKD. […] The complement system activation has a huge impact on DKD progression. […] Hyperglycaemia and its effects cause DNA damage, and display effects of ageing in patients with diabetes by causing chromosomal telomere shortening, resulting in proteinuria and DKD progression. […] The kidneys in a diabetic environment undergo many changes, from initial renal enlargement to vasoconstriction, endothelial and tubular cell injury, to eventual renal fibrosis.

• #27 Pathogenesis of Diabetic Nephropathy – Chronic Kidney Disease and Type 2 Diabetes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571720/

  Inflammation and fibrosis are important causes of diabetic nephropathy. Whether this is causal or in response to injury remains a matter of debate. However, there is a strong relation between the degree of infiltration of macrophages and subsequent occurrence of tubular interstitial fibrosis and progression of diabetic kidney disease. […] The pathogenesis of diabetic nephropathy involves metabolic, hemodynamic, growth, and inflammatory and fibrotic factors. The relative contributions of these factors vary among patients, over time, and even in different compartments of the kidney, and genetic and environmental factors can modify the appearance of the kidney lesions. AKI plays an important role in the progression of kidney disease in patients with diabetes. MR activation, particularly in the myeloid cells, may be important in mediating inflammation and fibrosis in CKD and after AKI in individuals with type 2 diabetes, and MR antagonist therapy may be protective.

• #28 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The increase in AGEs has been directly associated with an elevated expression of NLRP3-related proteins, which have been proposed as mediators of CKD, potentially activating mesangial cells. […] In summary, DKD involves multiple intertwined pathways, with inflammation also playing a pivotal role in its development. […] The major signaling pathways implicated in renal fibrosis encompass the TGF-β, MAPK, Wnt/β-catenin, PI3K/AKT, JAK/STAT, and Notch pathways. […] It is widely recognized that TGF-β stands as the most significant profibrotic cytokine, serving as a primary driver of renal fibrosis in DKD. […] The success of inhibiting TGF-β1 signaling in animal studies has prompted clinical investigations in DKD. […] The Wnt canonical and non-canonical pathways have been identified as another key player in the progression of DKD.

• #29

  https://www.jci.org/articles/view/72271

  Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. […] DKD is a prototypical disease of gene and environmental interactions. […] Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. […] While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. […] Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. […] The dysregulated metabolic milieu (including hyperglycemia, hyperlipidemia, and insulin resistance) initiates DKD.

• #30

  https://www.jci.org/articles/view/72271

  Multiple lines of evidence indicate that podocyte dropout is a critical factor for DKD development. […] Podocytes have received special interest as they cannot be replaced, indicating that their loss and injury represent an irreversible step in disease development. […] Excessive activation of mTORC1 likely mediates podocyte hypertrophy. […] The objective of this review is to focus on an early target of diabetic injury, the podocyte, with a more limited discussion of effects on the endothelium, mesangium, and tubulointerstitial compartments.

• #31 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  Endothelial cell damage is one of the earliest pathological changes in diabetic nephropathy. This damage generates reactive oxygen species, which are major contributors to the progression of diabetic nephropathy. […] Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. […] The polyol pathway contributes to diabetic nephropathy through the accumulation of fructose and sorbitol, glucose byproducts that increase osmotic pressure, leading to edema and cell membrane rupture. […] Genetics is crucial for the development of diabetic nephropathy, with both genetic and environmental factors contributing to its onset. […] Patients with T2D may present with albuminuria at the time of diabetes diagnosis, whereas diabetic nephropathy typically develops 15 to 20 years after the onset of T1D.

• #32

  https://www.jci.org/articles/view/72271

  Indeed the landmark DCCT (Diabetes Complications and Treatment) trial established that tight glucose control (HbA1c level of 7% vs. 9%) reduces the development of DKD by more than 50% in T1DM patients. […] Hyperglycemia also increases the non-enzymatic reaction of glucose and other glycating compounds derived both from glucose and from increased fatty acid oxidation, which generates advanced glycation end products in complication-prone cell types, including kidney cells. […] Increased reactive oxygen species (ROS) and superoxide generation by dysfunctional mitochondria in diabetes has been postulated as the primary initiating event in the development of diabetic complications. […] Podocyte loss may follow from hyperglycemia-induced ROS generation causing podocyte apoptosis or detachment.

• #33

  https://www.jci.org/articles/view/72271

  Multiple lines of evidence indicate that podocyte dropout is a critical factor for DKD development. […] Podocytes have received special interest as they cannot be replaced, indicating that their loss and injury represent an irreversible step in disease development. […] Excessive activation of mTORC1 likely mediates podocyte hypertrophy. […] The objective of this review is to focus on an early target of diabetic injury, the podocyte, with a more limited discussion of effects on the endothelium, mesangium, and tubulointerstitial compartments.

• #34 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  The earliest changes in DKD are due to hyperfiltration in the glomerulus, causing thickening and stiffness of the glomerular basement membrane from sheer pressure and deposition of extracellular matrix. […] Podocyte injury has been shown to mimic diabetic changes even in absence of hyperglycaemia, which indicates that podocyte injury is the key in development of DKD. […] The renal tubules, given their high metabolic demand, are rich in mitochondria. […] Unfortunately, all of the above mechanisms merge together and result ultimately in fibrosis and atrophic kidney tissue. […] Most of the pathway mediators that have been identified are potential targets to slow down DKD progression. […] Hyperglycaemia is probably the instigator for all the downstream effects leading to DKD. […] Understanding DKD at a molecular level helps with the ability to tailor management, as we try to prevent ESKD or complications of DKD.

• #35 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The increase in AGEs has been directly associated with an elevated expression of NLRP3-related proteins, which have been proposed as mediators of CKD, potentially activating mesangial cells. […] In summary, DKD involves multiple intertwined pathways, with inflammation also playing a pivotal role in its development. […] The major signaling pathways implicated in renal fibrosis encompass the TGF-β, MAPK, Wnt/β-catenin, PI3K/AKT, JAK/STAT, and Notch pathways. […] It is widely recognized that TGF-β stands as the most significant profibrotic cytokine, serving as a primary driver of renal fibrosis in DKD. […] The success of inhibiting TGF-β1 signaling in animal studies has prompted clinical investigations in DKD. […] The Wnt canonical and non-canonical pathways have been identified as another key player in the progression of DKD.

• #36 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The increase in AGEs has been directly associated with an elevated expression of NLRP3-related proteins, which have been proposed as mediators of CKD, potentially activating mesangial cells. […] In summary, DKD involves multiple intertwined pathways, with inflammation also playing a pivotal role in its development. […] The major signaling pathways implicated in renal fibrosis encompass the TGF-β, MAPK, Wnt/β-catenin, PI3K/AKT, JAK/STAT, and Notch pathways. […] It is widely recognized that TGF-β stands as the most significant profibrotic cytokine, serving as a primary driver of renal fibrosis in DKD. […] The success of inhibiting TGF-β1 signaling in animal studies has prompted clinical investigations in DKD. […] The Wnt canonical and non-canonical pathways have been identified as another key player in the progression of DKD.

• #37 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The increase in AGEs has been directly associated with an elevated expression of NLRP3-related proteins, which have been proposed as mediators of CKD, potentially activating mesangial cells. […] In summary, DKD involves multiple intertwined pathways, with inflammation also playing a pivotal role in its development. […] The major signaling pathways implicated in renal fibrosis encompass the TGF-β, MAPK, Wnt/β-catenin, PI3K/AKT, JAK/STAT, and Notch pathways. […] It is widely recognized that TGF-β stands as the most significant profibrotic cytokine, serving as a primary driver of renal fibrosis in DKD. […] The success of inhibiting TGF-β1 signaling in animal studies has prompted clinical investigations in DKD. […] The Wnt canonical and non-canonical pathways have been identified as another key player in the progression of DKD.

• #38 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The PI3K/AKT signaling pathway assumes a central regulatory role in the progression of DKD. […] The Notch signaling pathway in the mammalian system comprises four transmembrane receptors (Notch1–Notch4), two Jagged family ligands (JAG1 and JAG2), and three delta-like ligands (DLL1, DLL3, and DLL4). […] The MR functions as intracellular receptors, operating as a nuclear transcription factor or exerting rapid non-genomic effects through secondary cell signaling pathways. […] The MR instigates the inflammatory cascade by generating ROS through NADPH in the mitochondria, a process further amplified by Rac1. […] The role of OPN in DKD has been reviewed in detail by our group recently. […] Our findings gained further support from a recent investigation in the German Chronic Kidney Disease cohort.

• #39 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The PI3K/AKT signaling pathway assumes a central regulatory role in the progression of DKD. […] The Notch signaling pathway in the mammalian system comprises four transmembrane receptors (Notch1–Notch4), two Jagged family ligands (JAG1 and JAG2), and three delta-like ligands (DLL1, DLL3, and DLL4). […] The MR functions as intracellular receptors, operating as a nuclear transcription factor or exerting rapid non-genomic effects through secondary cell signaling pathways. […] The MR instigates the inflammatory cascade by generating ROS through NADPH in the mitochondria, a process further amplified by Rac1. […] The role of OPN in DKD has been reviewed in detail by our group recently. […] Our findings gained further support from a recent investigation in the German Chronic Kidney Disease cohort.

• #40 The analysis of risk factors for diabetic nephropathy progression and the construction of a prognostic database for chronic kidney diseases | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-2016-y

  Diabetic nephropathy (DN) affects about 40% of diabetes mellitus (DM) patients and is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) all over the world, especially in high- and middle-income countries. […] Currently, the treatment of DN is mainly to prevent or delay disease progression. […] Moreover, current animal/cell models could not replicate all the features of human DN, while the development of Epigenetics further demonstrates the complexity of the mechanism of DN progression. […] It is shown that the TNF signaling pathway plays a role through the process of DN progression and adipocytokine signaling pathway is uniquely enriched in ESRD. […] Molecules, such as TNF, IL6, SOD2, etc. are very important for DN progression, among which, it seems that AGER plays a pivotal role in the mechanism.

• #41 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The increase in AGEs has been directly associated with an elevated expression of NLRP3-related proteins, which have been proposed as mediators of CKD, potentially activating mesangial cells. […] In summary, DKD involves multiple intertwined pathways, with inflammation also playing a pivotal role in its development. […] The major signaling pathways implicated in renal fibrosis encompass the TGF-β, MAPK, Wnt/β-catenin, PI3K/AKT, JAK/STAT, and Notch pathways. […] It is widely recognized that TGF-β stands as the most significant profibrotic cytokine, serving as a primary driver of renal fibrosis in DKD. […] The success of inhibiting TGF-β1 signaling in animal studies has prompted clinical investigations in DKD. […] The Wnt canonical and non-canonical pathways have been identified as another key player in the progression of DKD.

• #42

  https://www.jci.org/articles/view/72271

  Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. […] DKD is a prototypical disease of gene and environmental interactions. […] Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. […] While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. […] Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. […] The dysregulated metabolic milieu (including hyperglycemia, hyperlipidemia, and insulin resistance) initiates DKD.

• #43 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  Endothelial cell damage is one of the earliest pathological changes in diabetic nephropathy. This damage generates reactive oxygen species, which are major contributors to the progression of diabetic nephropathy. […] Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. […] The polyol pathway contributes to diabetic nephropathy through the accumulation of fructose and sorbitol, glucose byproducts that increase osmotic pressure, leading to edema and cell membrane rupture. […] Genetics is crucial for the development of diabetic nephropathy, with both genetic and environmental factors contributing to its onset. […] Patients with T2D may present with albuminuria at the time of diabetes diagnosis, whereas diabetic nephropathy typically develops 15 to 20 years after the onset of T1D.

• #44

  https://www.jci.org/articles/view/165654

  Diabetic kidney disease (DKD) refers to the clinical diagnosis of kidney disease attributed to diabetes based on the presence of albuminuria (300 mg/d) and/or low estimated glomerular filtration rate (eGFR) (60 cc/min) in patients with type 2 diabetes, but an even lower threshold of albuminuria can signify DKD in patients with type 1 diabetes. […] Epidemiological studies indicate that around 40% of patients with diabetes develop DKD. […] Our understanding of DKD remains incomplete, in part because animal models poorly recapitulate human DKD. […] DKD has a strong heritable component. […] Epigenomic changes are proposed to be responsible for the metabolic memory. […] Methylation of DNA cytosines is an important epigenetic modification that can cause transcriptional repression. […] The importance of methylation in metabolic memory was suggested by the identification of methylation differences, for example in the TXNIP locus, in the Diabetes Complications Control Trial (DCCT) cohort.

• #45

  https://www.jci.org/articles/view/165654

  Diabetic kidney disease (DKD) refers to the clinical diagnosis of kidney disease attributed to diabetes based on the presence of albuminuria (300 mg/d) and/or low estimated glomerular filtration rate (eGFR) (60 cc/min) in patients with type 2 diabetes, but an even lower threshold of albuminuria can signify DKD in patients with type 1 diabetes. […] Epidemiological studies indicate that around 40% of patients with diabetes develop DKD. […] Our understanding of DKD remains incomplete, in part because animal models poorly recapitulate human DKD. […] DKD has a strong heritable component. […] Epigenomic changes are proposed to be responsible for the metabolic memory. […] Methylation of DNA cytosines is an important epigenetic modification that can cause transcriptional repression. […] The importance of methylation in metabolic memory was suggested by the identification of methylation differences, for example in the TXNIP locus, in the Diabetes Complications Control Trial (DCCT) cohort.

• #46

  https://www.jci.org/articles/view/165654

  Diabetic kidney disease (DKD) refers to the clinical diagnosis of kidney disease attributed to diabetes based on the presence of albuminuria (300 mg/d) and/or low estimated glomerular filtration rate (eGFR) (60 cc/min) in patients with type 2 diabetes, but an even lower threshold of albuminuria can signify DKD in patients with type 1 diabetes. […] Epidemiological studies indicate that around 40% of patients with diabetes develop DKD. […] Our understanding of DKD remains incomplete, in part because animal models poorly recapitulate human DKD. […] DKD has a strong heritable component. […] Epigenomic changes are proposed to be responsible for the metabolic memory. […] Methylation of DNA cytosines is an important epigenetic modification that can cause transcriptional repression. […] The importance of methylation in metabolic memory was suggested by the identification of methylation differences, for example in the TXNIP locus, in the Diabetes Complications Control Trial (DCCT) cohort.

• #47 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  The full-length OPN protein is cleaved by various proteases, including thrombin, matrix metalloproteinase (MMP)-3, MMP-7, cathepsin-D, and plasmin, producing ntOPN, which may have more detrimental effects in CKD. […] The interplay between genetic, epigenetic, and environmental factors in the initiation and progression of DKD has been illustrated in several studies. […] These findings emphasize the dynamic regulation of multiple signaling pathways by DNA methylation in the progression of DKD.

• #48

  https://link.springer.com/article/10.1007/s10557-017-6755-9

  Epigenetics is emerging as a next-generational paradigm to characterise DN. […] Altered DNA methylation profiles were detected in DN, and such investigations have documented differential methylation of various mediators of glomerular cell apoptosis. […] The ability to modulate metabolic memory may represent a powerful tool for the treatment of DN and other diseases. […] Despite the complex nature of DN, the underlying molecular mechanisms of DN have yet to be completely elucidated. […] Even though hyperglycaemia-induced TGF- upregulation has emerged as a central pathogenic mechanism in DN, research has highlighted the contributions of additional pleiotropic cellular events. […] Future efforts to refine our understanding of DN pathophysiology will be necessary to resolve the current debates, determine the relative importance of newly identified pathogenic mechanisms and prioritise novel therapeutic targets.

• #49 New Tubulocentric Insights for Diabetic Nephropathy: From Pathophysiology to Treatment | IntechOpen

  https://www.intechopen.com/chapters/62357

  The prevalence of diabetes is increasing worldwide, and one of the most important complications, diabetic nephropathy, constitutes a significant global health care and socioeconomic burden. Glomerular dysfunction is a major factor in the development and progression of diabetic nephropathy. However, emerging evidence suggests that tubular damage also plays an important role in the pathogenesis of diabetic nephropathy. […] This tubulocentric view shifts the focus markedly from glomeruli to proximal tubules, which might have an important role as a trigger or a driver in the early development and progression of diabetic nephropathy. […] These novel insights also provide new opportunities for diagnostic and therapeutic progress through targeting the proximal tubules in diabetic nephropathy.

• #50 New Tubulocentric Insights for Diabetic Nephropathy: From Pathophysiology to Treatment | IntechOpen

  https://www.intechopen.com/chapters/62357

  Recent studies revealed that glomerulopathy is preceded by tubular dysfunction during the development and progression of diabetic nephropathy. […] Pathological changes in the tubulointerstitium that have been linked to diabetic nephropathy include the thickening of the tubular basement membrane (TBM), tubular atrophy, interstitial fibrosis, and arteriosclerosis, which are closely correlated with the magnitude of renal dysfunction and albuminuria. […] Furthermore, such tubulointerstitial damage can cause a disconnect between the glomerulus and the proximal tubule, the so-called atubular glomerulus, which is an important and a common cause of irreversible CKD progression. […] Recent studies suggest that the glomerular dysfunction triggered by proximal tubules, the so-called retrograde trafficking might be important in diabetic nephropathy.

• #51

  https://journals.lww.com/md-journal/fulltext/2023/07280/pathophysiology_of_diabetic_kidney_disease_and.46.aspx

  In diabetic nephropathy, excessive energy supply inhibits autophagy protection in the kidney, leading to accumulation of damaged proteins and organelles and aggravating the progression of diabetic nephropathy. […] These data suggest that impaired autophagy may be involved in the pathogenesis of DKD, and autophagy activation is promising as a potential therapy for the treatment of DKD. […] Although an increasing number of studies have confirmed that the development of DKD is influenced by factors such as genetics, energy supply, oxidative stress as well as autophagic activity and regulation of autophagy-related signaling molecules has also received increasing attention, the role of autophagy in the development of DKD remains inadequately, and more experiments are needed to further improve this field.

• #52

  https://journals.lww.com/jasn/abstract/9900/deficiency_of_gadd45__r_loop_pathway_and_kidney.588.aspx

  Growth arrest and DNA damageinducible 45 (GADD45) is crucial for maintaining kidney health by enhancing six-transmembrane epithelial antigen of the prostate 4 expression through promoter demethylation. […] In diabetic nephropathy, lower GADD45 levels hinder R-loop formation, leading to decreased six-transmembrane epithelial antigen of the prostate 4 demethylation and expression. […] Targeting the GADD45-R-loop pathway holds promise for innovative diabetic nephropathy treatment strategies. […] Diabetic nephropathy is a primary cause of kidney failure. Persistent hyperglycemia causes metabolic perturbations epigenetically dysregulating gene expression in kidney cells, thereby leading to diabetic nephropathy pathogenesis. […] GADD45 expression was reduced in kidneys of diabetic nephropathy, correlating with kidney dysfunction.

• #53

  https://journals.lww.com/jasn/abstract/9900/deficiency_of_gadd45__r_loop_pathway_and_kidney.588.aspx

  GADD45 knockout worsened kidney injuries, while overexpression mitigated them. […] Mechanistically, GADD45 interacted with R-loops on the six-transmembrane epithelial antigen of the prostate 4 (STEAP4) promoter, recruiting ten eleven translocation 1 to activate STEAP4 transcription. […] Deficiency in the GADD45-R-loop pathway exacerbated mitochondrial injury, disrupted lipid metabolism, and increased oxidative stress in diabetic nephropathy. […] Deficiency of GADD45 exacerbates diabetic nephropathy by interacting with R-loops and inhibiting STEAP4 promoter demethylation. […] Targeting the GADD45-R-loop pathway offers therapeutic potential against diabetic nephropathy.

• #54 Body Water Distribution and 25-hydroxyvitamin D in T2DM | DMSO

  https://www.dovepress.com/association-between-the-water-distribution-in-the-human-body-and-25-hy-peer-reviewed-fulltext-article-DMSO

  A correlation between vitamin D and water distribution was observed, and a high ECW/TBW was one of the pathways through which low vitamin D levels might affect DN. […] In this cross-sectional study involving 533 inpatients, for the first time, we have demonstrated a negative correlation between the ECW/TBW and 25-hydroxyvitamin D levels in the T2DM population according to linear regression analyses, proposing a preliminary theory that changing the water distribution in the human body is a potential mechanism by which low 25-hydroxyvitamin D levels may be associated with DN. […] Regarding the total effect of vitamin D on DN, the mediation effect of the water distribution accounted for 15.44%. […] The mediation analysis suggested that there was a statistical correlation between vitamin D and DN, whether through the total effect, the direct effect, or the indirect effect of the ECW/TBW of the whole body.

• #55 Pathogenesis of Diabetic Nephropathy – Chronic Kidney Disease and Type 2 Diabetes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571720/

  Our understanding of the natural history of diabetic nephropathy has emerged largely from patients with type 1 diabetes. However, histological manifestations among those with type 2 diabetes are similar. Both the clinical manifestations and the histological appearances of kidney disease associated with diabetes have been well characterized. The pathogenesis, however, is less well understood, and there are gaps in our understanding of how various causal factors relate to the histological manifestations of diabetes; in part, this is because of a paucity of kidney biopsies and longitudinal data. Here, we will focus on the pathogenesis, summarizing our current understanding of the histological and clinical correlates and pointing out remaining controversies in the context of pathogenesis. […] The pathogenesis of diabetic nephropathy is initiated and maintained by four causal factors, which can be classified broadly into metabolic, hemodynamic, growth, and proinflammatory or profibrotic factors. Although there is both a substantial overlap among these factors and variability in their relative contribution among individuals and over time, for ease of discussion, we will describe the pathogenesis as if each factor played an isolated role. These pathogenetic factors produce lesions in various kidney compartments: glomeruli, tubuli, interstitium, and vasculature. A complex series of molecules, receptors, enzymes, and transcription factors participate in the process that drives the earliest stages of kidney disease to an enlarged kidney with hypertrophy, expanded extracellular matrix (ECM), glomerulosclerosis, vascular hyalinosis, interstitial fibrosis and tubular atrophy, and loss of function culminating in end-stage renal disease (ESRD).

• #56 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  Diabetic kidney disease (DKD) has been an immense burden on the healthcare system, and is the leading cause of end stage kidney disease worldwide. DKD involves various intersecting pathways that lead to progressive kidney damage. […] Due to its versatile pathogenesis, DKD has been a formidable adversary. […] The end result of uncontrolled hyperglycaemia in the kidney is nephron death. This manifests in the form of glomerulosclerosis, interstitial fibrosis, and tubular atrophy, but there are a lot of milestones and instigators along the way. […] Hyperglycaemia leads to hyperfiltration, which is followed by metabolic, hormonal, haemodynamic, inflammatory and epigenetic changes. Oxidative stress and hypoxia play a vital role. All these precipitate to podocyte injury, mitochondrial distress, tissue death, glomerulosclerosis, and interstitial fibrosis.

• #57 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  Endothelial cell damage is one of the earliest pathological changes in diabetic nephropathy. This damage generates reactive oxygen species, which are major contributors to the progression of diabetic nephropathy. […] Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. […] The polyol pathway contributes to diabetic nephropathy through the accumulation of fructose and sorbitol, glucose byproducts that increase osmotic pressure, leading to edema and cell membrane rupture. […] Genetics is crucial for the development of diabetic nephropathy, with both genetic and environmental factors contributing to its onset. […] Patients with T2D may present with albuminuria at the time of diabetes diagnosis, whereas diabetic nephropathy typically develops 15 to 20 years after the onset of T1D.

• #58

  https://link.springer.com/article/10.1007/s10557-017-6755-9

  A common feature of diabetic cardiovascular complications is diffuse endothelial injury, and DN is no exception. […] The myofibroblast represents another principal mediator of DN. […] Recent papers have demonstrated a key role for the Snail transcription factor in kidney fibrosis and suggest that epithelial cells undergo a partial EMT without continuing to the myofibroblast population. […] It is now clear that the pathophysiology underpinning DN is a complex multi-molecular, multi-cellular process and therefore, targeting therapeutic strategies around more than one of these pathological targets may be a sensible approach. […] For years, researchers have focused on the pivotal role of hyperglycaemia in the development of diabetic vascular complications. […] However, it is known that DN can develop even in those patients who show optimal blood glucose control.

• #59 Diabetic Nephropathy: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238946-overview

  Diabetic nephropathy is a clinical syndrome characterized by the following: Persistent albuminuria (300 mg/d or 200 g/min) that is confirmed on at least 2 occasions 3-6 months apart. […] The key change in diabetic glomerulopathy is augmentation of extracellular matrix. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix. […] Evidence suggests that hypertension associated with obesity, metabolic syndrome, and diabetes may play an important role in the pathogenesis of diabetic nephropathy. […] The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycation products, and activation of cytokines.

• #60 Diabetic Nephropathy: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238946-overview

  Hyperglycemia also increases the expression of transforming growth factor- (TGF-) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF- and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy. […] A study by Bherwani et al suggested that an association exists between decreased serum folic acid levels and diabetic nephropathy.

• #61 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Renal fibrosis is recognised as a key hallmark in the progression of DKD, particularly in driving renal structural changes especially extracellular matrix (ECM) accumulation causing renal injury. High glucose conditions have been found to enhance the activation of profibrotic growth factors including connective tissue growth factor (CTGF) as well as transforming growth factor-β (TGF-β) which recruits and activates extracellular matrix-producing cells. […] Albuminuria is recognised as an early predictor for the progression of DKD. The variety of pathological mechanisms including oxidative stress, renal inflammation, fibrosis and haemodynamic alterations lead to the damage of the highly regulated glomerular filtration barrier, compromising the filtration process. Damage to the glomerular basement membrane, particularly to the podocytes which uphold the structural integrity of the filtration barrier is an early feature in the progression of DKD.

• #62 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  Endothelial cell damage is one of the earliest pathological changes in diabetic nephropathy. This damage generates reactive oxygen species, which are major contributors to the progression of diabetic nephropathy. […] Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. […] The polyol pathway contributes to diabetic nephropathy through the accumulation of fructose and sorbitol, glucose byproducts that increase osmotic pressure, leading to edema and cell membrane rupture. […] Genetics is crucial for the development of diabetic nephropathy, with both genetic and environmental factors contributing to its onset. […] Patients with T2D may present with albuminuria at the time of diabetes diagnosis, whereas diabetic nephropathy typically develops 15 to 20 years after the onset of T1D.

• #63 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  The earliest changes in DKD are due to hyperfiltration in the glomerulus, causing thickening and stiffness of the glomerular basement membrane from sheer pressure and deposition of extracellular matrix. […] Podocyte injury has been shown to mimic diabetic changes even in absence of hyperglycaemia, which indicates that podocyte injury is the key in development of DKD. […] The renal tubules, given their high metabolic demand, are rich in mitochondria. […] Unfortunately, all of the above mechanisms merge together and result ultimately in fibrosis and atrophic kidney tissue. […] Most of the pathway mediators that have been identified are potential targets to slow down DKD progression. […] Hyperglycaemia is probably the instigator for all the downstream effects leading to DKD. […] Understanding DKD at a molecular level helps with the ability to tailor management, as we try to prevent ESKD or complications of DKD.

• #64 Pathogenesis of diabetic kidney disease

  https://www.degruyterbrill.com/document/doi/10.2478/dine-2021-0004/html?srsltid=AfmBOooRUbi93sSokG57HWhgqkD-kaBxSj6pY0QJwcfZEX_3eymeHA-x

  Inflammatory processes and immune cells are involved in the development and progression of DN. Glomerular and interstitial infiltration by monocytes/macrophages and activated T lymphocytes as well as heightened Nlrp-3 inflammasome activation are observed both in human and experimental DN. […] Widening of the glomerular basement membrane (GBM) is associated with accumulation of type IV collagen and a net reduction in negatively charged heparin sulfate proteoglycan. The expression of one permeability-controlling protein, nephrin, is abnormally low in DN. […] Although glomerulosclerosis is a cardinal feature of DN, tubulointerstitial injury ultimately determines the rate of attrition of renal function. […] In patients with DN, Ang II has many nonhemodynamic effects and mediates cell proliferation, hypertrophy, ECM expansion, and cytokine (TGF-, VEGF) synthesis. […] Increasing evidence shows epigenetic mechanisms, involving chromatin histone modifications, DNA methylation, and non-coding RNAs contribute to the development of DN. […] Lipotoxicity is another pathway that is increasingly implicated in DN.

• #65 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Oxidative stress plays a critical role in the initiation and progression of DKD. Chronic hyperglycaemia induces oxidative stress via enhanced reactive oxygen species (ROS) production and diminished antioxidant defence in DKD. Chronic hyperglycaemia disrupts the homeostatic balance between pro-oxidant and antioxidant pathways whereby there is an upregulation of pro-oxidant enzyme-derived ROS formation and an accompanied reduction in antioxidants, causing oxidative stress within the kidneys. Recent accumulating evidence demonstrates the overproduction of intrarenal ROS in diabetes and subsequent haemodynamic alterations and metabolic changes as a key mediator and a common denominator of the pathways leading to disrupted renal function and pathological structural changes in DKD. […] In DKD, inflammation plays an important role. It is driven by multiple pathways including oxidative stress, activation of transcription pathways such as JAK/STAT and transcription factors including nuclear factor κB (NF-κB) and the activation of pro-inflammatory cytokines.

• #66 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Oxidative stress plays a critical role in the initiation and progression of DKD. Chronic hyperglycaemia induces oxidative stress via enhanced reactive oxygen species (ROS) production and diminished antioxidant defence in DKD. Chronic hyperglycaemia disrupts the homeostatic balance between pro-oxidant and antioxidant pathways whereby there is an upregulation of pro-oxidant enzyme-derived ROS formation and an accompanied reduction in antioxidants, causing oxidative stress within the kidneys. Recent accumulating evidence demonstrates the overproduction of intrarenal ROS in diabetes and subsequent haemodynamic alterations and metabolic changes as a key mediator and a common denominator of the pathways leading to disrupted renal function and pathological structural changes in DKD. […] In DKD, inflammation plays an important role. It is driven by multiple pathways including oxidative stress, activation of transcription pathways such as JAK/STAT and transcription factors including nuclear factor κB (NF-κB) and the activation of pro-inflammatory cytokines.

• #67

  https://journals.lww.com/md-journal/fulltext/2023/07280/pathophysiology_of_diabetic_kidney_disease_and.46.aspx

  Diabetic kidney disease (DKD) is one of the main complications of diabetic microangiopathy. The pathogenesis of DKD is very complex, including autophagy, inflammation, oxidative stress. Although a series of treatment intervention have achieved certain results in the treatment of diabetic nephropathy, still cannot reverse the kidney injury of diabetic nephropathy. […] Under high glucose conditions, mitochondrial fragments accumulate in the kidney, suggesting that mitochondrial clearance mechanisms may be attenuated with changes in mitochondrial transformation mechanisms. However, the exact mechanism of mitophagy regulation in DKD has not been elucidated. Recent advances in autophagy have renewed interest in these signaling pathways and molecules in the pathogenesis of DKD. Investigating autophagy and its associated signaling molecules may provide potential unique targets for therapeutic intervention in DKD.

• #68 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  The earliest changes in DKD are due to hyperfiltration in the glomerulus, causing thickening and stiffness of the glomerular basement membrane from sheer pressure and deposition of extracellular matrix. […] Podocyte injury has been shown to mimic diabetic changes even in absence of hyperglycaemia, which indicates that podocyte injury is the key in development of DKD. […] The renal tubules, given their high metabolic demand, are rich in mitochondria. […] Unfortunately, all of the above mechanisms merge together and result ultimately in fibrosis and atrophic kidney tissue. […] Most of the pathway mediators that have been identified are potential targets to slow down DKD progression. […] Hyperglycaemia is probably the instigator for all the downstream effects leading to DKD. […] Understanding DKD at a molecular level helps with the ability to tailor management, as we try to prevent ESKD or complications of DKD.

• #69 Pathogenesis of Diabetic Nephropathy – Chronic Kidney Disease and Type 2 Diabetes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571720/

  Inflammation and fibrosis are important causes of diabetic nephropathy. Whether this is causal or in response to injury remains a matter of debate. However, there is a strong relation between the degree of infiltration of macrophages and subsequent occurrence of tubular interstitial fibrosis and progression of diabetic kidney disease. […] The pathogenesis of diabetic nephropathy involves metabolic, hemodynamic, growth, and inflammatory and fibrotic factors. The relative contributions of these factors vary among patients, over time, and even in different compartments of the kidney, and genetic and environmental factors can modify the appearance of the kidney lesions. AKI plays an important role in the progression of kidney disease in patients with diabetes. MR activation, particularly in the myeloid cells, may be important in mediating inflammation and fibrosis in CKD and after AKI in individuals with type 2 diabetes, and MR antagonist therapy may be protective.

• #70 Pathogenesis of diabetic kidney disease

  https://www.degruyterbrill.com/document/doi/10.2478/dine-2021-0004/html?srsltid=AfmBOooRUbi93sSokG57HWhgqkD-kaBxSj6pY0QJwcfZEX_3eymeHA-x

  Inflammatory processes and immune cells are involved in the development and progression of DN. Glomerular and interstitial infiltration by monocytes/macrophages and activated T lymphocytes as well as heightened Nlrp-3 inflammasome activation are observed both in human and experimental DN. […] Widening of the glomerular basement membrane (GBM) is associated with accumulation of type IV collagen and a net reduction in negatively charged heparin sulfate proteoglycan. The expression of one permeability-controlling protein, nephrin, is abnormally low in DN. […] Although glomerulosclerosis is a cardinal feature of DN, tubulointerstitial injury ultimately determines the rate of attrition of renal function. […] In patients with DN, Ang II has many nonhemodynamic effects and mediates cell proliferation, hypertrophy, ECM expansion, and cytokine (TGF-, VEGF) synthesis. […] Increasing evidence shows epigenetic mechanisms, involving chromatin histone modifications, DNA methylation, and non-coding RNAs contribute to the development of DN. […] Lipotoxicity is another pathway that is increasingly implicated in DN.

• #71 Pathogenesis of diabetic kidney disease

  https://www.degruyterbrill.com/document/doi/10.2478/dine-2021-0004/html?srsltid=AfmBOooRUbi93sSokG57HWhgqkD-kaBxSj6pY0QJwcfZEX_3eymeHA-x

  Inflammatory processes and immune cells are involved in the development and progression of DN. Glomerular and interstitial infiltration by monocytes/macrophages and activated T lymphocytes as well as heightened Nlrp-3 inflammasome activation are observed both in human and experimental DN. […] Widening of the glomerular basement membrane (GBM) is associated with accumulation of type IV collagen and a net reduction in negatively charged heparin sulfate proteoglycan. The expression of one permeability-controlling protein, nephrin, is abnormally low in DN. […] Although glomerulosclerosis is a cardinal feature of DN, tubulointerstitial injury ultimately determines the rate of attrition of renal function. […] In patients with DN, Ang II has many nonhemodynamic effects and mediates cell proliferation, hypertrophy, ECM expansion, and cytokine (TGF-, VEGF) synthesis. […] Increasing evidence shows epigenetic mechanisms, involving chromatin histone modifications, DNA methylation, and non-coding RNAs contribute to the development of DN. […] Lipotoxicity is another pathway that is increasingly implicated in DN.

• #72 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Renal fibrosis is recognised as a key hallmark in the progression of DKD, particularly in driving renal structural changes especially extracellular matrix (ECM) accumulation causing renal injury. High glucose conditions have been found to enhance the activation of profibrotic growth factors including connective tissue growth factor (CTGF) as well as transforming growth factor-β (TGF-β) which recruits and activates extracellular matrix-producing cells. […] Albuminuria is recognised as an early predictor for the progression of DKD. The variety of pathological mechanisms including oxidative stress, renal inflammation, fibrosis and haemodynamic alterations lead to the damage of the highly regulated glomerular filtration barrier, compromising the filtration process. Damage to the glomerular basement membrane, particularly to the podocytes which uphold the structural integrity of the filtration barrier is an early feature in the progression of DKD.

• #73 Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000902

  Objective Glomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). […] This study examined diabetic kidney disease (DKD), which is a clinical diagnosis of diabetic damage due to diabetes mellitus. […] The typical clinical course of classical diabetic nephropathy is as follows: microalbuminuria develops, progresses to macroalbuminuria and sometimes leads to nephrotic syndrome. Eventually, the glomerular filtration rate (GFR) decreases and patients develop ESRD. However, recent epidemiological studies showed that many patients with diabetes develop decreased GFR without albuminuria. […] In the light of the fact that a certain proportion of patients with diabetes do not show the typical clinical course, those whose albuminuria is 30 mg/gCr and/or estimated GFR (eGFR) is 60 mL/min/1.73 m and whose primary disease is diabetes are now considered to have DKD.

• #74 Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000902

  Objective Glomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). […] This study examined diabetic kidney disease (DKD), which is a clinical diagnosis of diabetic damage due to diabetes mellitus. […] The typical clinical course of classical diabetic nephropathy is as follows: microalbuminuria develops, progresses to macroalbuminuria and sometimes leads to nephrotic syndrome. Eventually, the glomerular filtration rate (GFR) decreases and patients develop ESRD. However, recent epidemiological studies showed that many patients with diabetes develop decreased GFR without albuminuria. […] In the light of the fact that a certain proportion of patients with diabetes do not show the typical clinical course, those whose albuminuria is 30 mg/gCr and/or estimated GFR (eGFR) is 60 mL/min/1.73 m and whose primary disease is diabetes are now considered to have DKD.

• #75 Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan | BMJ Open Diabetes Research & Care

  https://drc.bmj.com/content/8/1/e000902

  Furthermore, a certain number of patients with diabetes show rapid declines in kidney function in a unidirectional process and are termed early decliners. […] A new concept called DKD is advocated that also included the albuminuria-free patients. […] We revealed the prevalence and risk factors of DKD with 2385 patients with diabetes in Japan and identified the pattern of estimated glomerular filtration rate (eGFR) variation and risk factors of early decliners during approximately 3 years of follow-up. […] Risk factors of early decliners with a normal baseline eGFR (60 mL/min/1.73 m) were calculated by multiple regression analysis with eGFR variation. […] A higher ACR level reportedly predicts an eGFR decline and ESRD. […] These results will help us recognize early decliners by observing eGFR decline rate for approximately 3 years and risk factors such as a high SBP, high ACR, and older age to allow for early intervention in high-risk patients.

• #76

  https://www.jci.org/articles/view/72271

  Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. […] DKD is a prototypical disease of gene and environmental interactions. […] Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. […] While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. […] Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. […] The dysregulated metabolic milieu (including hyperglycemia, hyperlipidemia, and insulin resistance) initiates DKD.

• #77

  https://www.jci.org/articles/view/72271

  Indeed the landmark DCCT (Diabetes Complications and Treatment) trial established that tight glucose control (HbA1c level of 7% vs. 9%) reduces the development of DKD by more than 50% in T1DM patients. […] Hyperglycemia also increases the non-enzymatic reaction of glucose and other glycating compounds derived both from glucose and from increased fatty acid oxidation, which generates advanced glycation end products in complication-prone cell types, including kidney cells. […] Increased reactive oxygen species (ROS) and superoxide generation by dysfunctional mitochondria in diabetes has been postulated as the primary initiating event in the development of diabetic complications. […] Podocyte loss may follow from hyperglycemia-induced ROS generation causing podocyte apoptosis or detachment.

• #78 Diabetic Nephropathy – a Review of Risk Factors, Progression, Mechanism, and Dietary Management

  https://www.biomolther.org/journal/view.html?doi=10.4062/biomolther.2020.204

  The role of SGLT2 and renin in these systems might help to answer the reasons for the effects of SGLT2 and RAS inhibition over a very short period on renal hemodynamics in diabetic kidney disease (DKD) patients. […] In DN, hyperglycemia-induced metabolic destruction is the major reason for the development and progression of diabetic nephropathy. […] The crucial factors for the existence of microalbuminuria in T2DM patients are high urinary albumin to creatinine ratio, high HbA1c level, older age hypertension, and increased blood glucose levels. […] Good control of the HbA1c level can avoid progression to ESRD and it demonstrates the significance of hyperglycemia in the development of DKD in T1DM patients. […] The risk factors for DKD are identified as low birth weight, morbid obesity, glycemic control, and genetic susceptibility which interprets that not all DM patients are interconnected to DKD.

• #79 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  The 3 main pathological lesions of diabetic nephropathy include diffuse mesangial cell expansion, GBM thickening, and arteriolar hyalinization. […] Hyperfiltration is one of the earliest pathological changes observed in diabetic nephropathy, involving both the glomeruli and renal tubules. […] Abnormal renal pathology is evident even before the onset of microalbuminuria. Characteristic lesions observed on light microscopy include thickened glomerular and tubular basement membranes, diffuse mesangial expansion, and arteriolar hyalinosis. […] A longer duration of diabetes mellitus, poor glycemic control, and uncontrolled hypertension are significant risk factors for developing diabetic nephropathy. […] Diabetic nephropathy is associated with high morbidity and mortality. Microalbuminuria is an independent risk factor for cardiovascular mortality, and the majority of patients ultimately die from ESRD.

• #80 Pathomechanisms of Diabetic Kidney Disease

  https://www.mdpi.com/2077-0383/12/23/7349

  While conventional approaches like optimal blood pressure control through renin–angiotensin–aldosterone system (RAAS) blockade and glycemic control have demonstrated efficacy in slowing down the progression of DKD, they do not halt or reverse the condition. […] The PKC pathway is associated with the advancement of DKD by narrowing small blood vessels in the kidney and thus affecting the function of glomeruli. […] In DKD, expansion of the glomerular basement membrane (GBM) and the accumulation of ECM are notable features. […] Transforming growth factor β1 (TGF-β1) plays a significant role in the accumulation of GBM and ECM in DKD. […] The activation of PKC overexpression is implicated in ECM accumulation, primarily arising from mesangial cells. […] The role of inflammation in the progression of DKD is significant, with various inflammatory cytokines contributing to renal injury.

• #81 Diabetic Kidney Disease: Diagnosis, Treatment, and Prevention | AAFP

  https://www.aafp.org/pubs/afp/issues/2019/0615/p751.html

  Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) delay and reduce the progression of DKD. A 2012 Cochrane review concluded that ACE inhibitors reduce the risk of new onset microalbuminuria or macroalbuminuria in individuals with diabetes with or without hypertension. The same review found that ACE inhibitors reduce the risk of death in patients with diabetes compared with placebo.

• #82 Diabetic Nephropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534200/

  The 3 main pathological lesions of diabetic nephropathy include diffuse mesangial cell expansion, GBM thickening, and arteriolar hyalinization. […] Hyperfiltration is one of the earliest pathological changes observed in diabetic nephropathy, involving both the glomeruli and renal tubules. […] Abnormal renal pathology is evident even before the onset of microalbuminuria. Characteristic lesions observed on light microscopy include thickened glomerular and tubular basement membranes, diffuse mesangial expansion, and arteriolar hyalinosis. […] A longer duration of diabetes mellitus, poor glycemic control, and uncontrolled hypertension are significant risk factors for developing diabetic nephropathy. […] Diabetic nephropathy is associated with high morbidity and mortality. Microalbuminuria is an independent risk factor for cardiovascular mortality, and the majority of patients ultimately die from ESRD.

• #83 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  The earliest changes in DKD are due to hyperfiltration in the glomerulus, causing thickening and stiffness of the glomerular basement membrane from sheer pressure and deposition of extracellular matrix. […] Podocyte injury has been shown to mimic diabetic changes even in absence of hyperglycaemia, which indicates that podocyte injury is the key in development of DKD. […] The renal tubules, given their high metabolic demand, are rich in mitochondria. […] Unfortunately, all of the above mechanisms merge together and result ultimately in fibrosis and atrophic kidney tissue. […] Most of the pathway mediators that have been identified are potential targets to slow down DKD progression. […] Hyperglycaemia is probably the instigator for all the downstream effects leading to DKD. […] Understanding DKD at a molecular level helps with the ability to tailor management, as we try to prevent ESKD or complications of DKD.

• #84 Diabetic Nephropathy – a Review of Risk Factors, Progression, Mechanism, and Dietary Management

  https://www.biomolther.org/journal/view.html?uid=1312&vmd=Full&

  DN is a significant DM microvascular disorder responsible for 50% of all ESRD populations. […] The use of stem cell therapy has been extensively studied for treating several diseases such as cardiac, immunological, renal, and neurological diseases. […] The use of stem cells for kidney disorders is also a potential therapeutic approach.

• #85 Diabetic Nephropathy – a Review of Risk Factors, Progression, Mechanism, and Dietary Management

  https://www.biomolther.org/journal/view.html?doi=10.4062/biomolther.2020.204

  A thorough discussion of different diabetic nephropathy treatment approaches is presented in this study. […] The use of stem cell therapy has been extensively studied for treating several diseases such as cardiac, immunological, renal, and neurological diseases. […] The use of stem cells for kidney disorders is also a potential therapeutic approach. […] Our review suggests the early diagnosis of microalbuminuria will help to identify patients with DN at the earliest.

• #86

  https://journals.lww.com/jasn/abstract/9900/deficiency_of_gadd45__r_loop_pathway_and_kidney.588.aspx

  Growth arrest and DNA damageinducible 45 (GADD45) is crucial for maintaining kidney health by enhancing six-transmembrane epithelial antigen of the prostate 4 expression through promoter demethylation. […] In diabetic nephropathy, lower GADD45 levels hinder R-loop formation, leading to decreased six-transmembrane epithelial antigen of the prostate 4 demethylation and expression. […] Targeting the GADD45-R-loop pathway holds promise for innovative diabetic nephropathy treatment strategies. […] Diabetic nephropathy is a primary cause of kidney failure. Persistent hyperglycemia causes metabolic perturbations epigenetically dysregulating gene expression in kidney cells, thereby leading to diabetic nephropathy pathogenesis. […] GADD45 expression was reduced in kidneys of diabetic nephropathy, correlating with kidney dysfunction.

• #87 Diabetic nephropathy (kidney disease) – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diabetic-nephropathy/diagnosis-treatment/drc-20354562

  Diabetic nephropathy usually is diagnosed during the regular testing that’s part of managing diabetes. […] The first step in treating diabetic nephropathy is to treat and control diabetes and high blood pressure. […] In the early stages of diabetic nephropathy, your treatment might include medicines to manage the following: […] Finerenone (Kerendia) might help reduce tissue scarring in diabetic nephropathy. […] In the future, people with diabetic nephropathy may benefit from treatments being developed using techniques that help the body repair itself, called regenerative medicine. […] These techniques may help reverse or slow kidney damage.

• #88 Diabetic nephropathy (kidney disease) – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diabetic-nephropathy/diagnosis-treatment/drc-20354562

  Diabetic nephropathy usually is diagnosed during the regular testing that’s part of managing diabetes. […] The first step in treating diabetic nephropathy is to treat and control diabetes and high blood pressure. […] In the early stages of diabetic nephropathy, your treatment might include medicines to manage the following: […] Finerenone (Kerendia) might help reduce tissue scarring in diabetic nephropathy. […] In the future, people with diabetic nephropathy may benefit from treatments being developed using techniques that help the body repair itself, called regenerative medicine. […] These techniques may help reverse or slow kidney damage.

• #89 Protective effect of paeoniflorin in diabetic nephropathy: A preclinical systematic review revealing the mechanism of action | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282275

  The study suggested that PF could inhibit renal inflammatory responses and improve the peroxidation status in DN rats via the SIRT1/Nrf2 signaling pathway, thereby alleviating the degree of renal tissue injury and exerting reno-protective effects. […] Our study showed that PF could inhibit the proteins downstream of TLR2/4 and JAK2/STAT3 signaling pathways including MyD88, p-IRAK-1, NF-B-p-p65, Trif, and p-IRF3, and also reduce the expressions of macrophage inflammatory factors including TNF-, MCP-1, IL-1, and iNOS. […] The present study demonstrates that PF exerts reno-protective effects in animal models of DN by promoting antioxidant effects, inhibiting macrophage infiltration activation, suppressing inflammatory responses, reducing mesangial cell proliferation, inhibiting endothelial proliferation, attenuating mesangial expansion and tubulointerstitial injury, and inhibiting TLR2 / 4 signaling pathway activation.

• #90 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  The earliest changes in DKD are due to hyperfiltration in the glomerulus, causing thickening and stiffness of the glomerular basement membrane from sheer pressure and deposition of extracellular matrix. […] Podocyte injury has been shown to mimic diabetic changes even in absence of hyperglycaemia, which indicates that podocyte injury is the key in development of DKD. […] The renal tubules, given their high metabolic demand, are rich in mitochondria. […] Unfortunately, all of the above mechanisms merge together and result ultimately in fibrosis and atrophic kidney tissue. […] Most of the pathway mediators that have been identified are potential targets to slow down DKD progression. […] Hyperglycaemia is probably the instigator for all the downstream effects leading to DKD. […] Understanding DKD at a molecular level helps with the ability to tailor management, as we try to prevent ESKD or complications of DKD.

• #91 Pathophysiology of Diabetic Kidney Disease – European Medical Journal

  https://www.emjreviews.com/nephrology/article/pathophysiology-of-diabetic-kidney-disease-j120121/

  The earliest changes in DKD are due to hyperfiltration in the glomerulus, causing thickening and stiffness of the glomerular basement membrane from sheer pressure and deposition of extracellular matrix. […] Podocyte injury has been shown to mimic diabetic changes even in absence of hyperglycaemia, which indicates that podocyte injury is the key in development of DKD. […] The renal tubules, given their high metabolic demand, are rich in mitochondria. […] Unfortunately, all of the above mechanisms merge together and result ultimately in fibrosis and atrophic kidney tissue. […] Most of the pathway mediators that have been identified are potential targets to slow down DKD progression. […] Hyperglycaemia is probably the instigator for all the downstream effects leading to DKD. […] Understanding DKD at a molecular level helps with the ability to tailor management, as we try to prevent ESKD or complications of DKD.

• #92 Pathogenesis of Diabetic Nephropathy – Chronic Kidney Disease and Type 2 Diabetes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571720/

  Our understanding of the natural history of diabetic nephropathy has emerged largely from patients with type 1 diabetes. However, histological manifestations among those with type 2 diabetes are similar. Both the clinical manifestations and the histological appearances of kidney disease associated with diabetes have been well characterized. The pathogenesis, however, is less well understood, and there are gaps in our understanding of how various causal factors relate to the histological manifestations of diabetes; in part, this is because of a paucity of kidney biopsies and longitudinal data. Here, we will focus on the pathogenesis, summarizing our current understanding of the histological and clinical correlates and pointing out remaining controversies in the context of pathogenesis. […] The pathogenesis of diabetic nephropathy is initiated and maintained by four causal factors, which can be classified broadly into metabolic, hemodynamic, growth, and proinflammatory or profibrotic factors. Although there is both a substantial overlap among these factors and variability in their relative contribution among individuals and over time, for ease of discussion, we will describe the pathogenesis as if each factor played an isolated role. These pathogenetic factors produce lesions in various kidney compartments: glomeruli, tubuli, interstitium, and vasculature. A complex series of molecules, receptors, enzymes, and transcription factors participate in the process that drives the earliest stages of kidney disease to an enlarged kidney with hypertrophy, expanded extracellular matrix (ECM), glomerulosclerosis, vascular hyalinosis, interstitial fibrosis and tubular atrophy, and loss of function culminating in end-stage renal disease (ESRD).

• #93 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  The pathophysiology of DKD is multifactorial in that the diabetes-induced hyperglycaemia drives various pathological pathways within the kidney which can be broadly characterised as haemodynamic, metabolic, inflammatory, fibrotic and oxidative stress as the major determinant of this pathological process. There is a substantial overlap and a dynamic interplay among these pathways, which occur in multiple renal compartments such as glomerular, vasculature, tubular and interstitium that drive the pathogenesis of DKD. The key features of diabetes-mediated renal complications include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function.

• #94 Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

  https://www.mdpi.com/2227-9059/12/5/1098

  Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

• #95 Diabetic kidney disease | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201518

  The kidney is arguably the most important target of microvascular damage in diabetes. A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease and/or other co-morbidity, including hypertension and ageing-related nephron loss. […] Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the reninangiotensinaldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. […] In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression. […] Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. […] A detailed review of the pathobiology of DKD. […] A detailed review of the molecular biology of diabetic complications.

• #96

  https://www.jci.org/articles/view/165654

  Changes in cellular metabolism in DKD. […] DKD is a primary microvascular complication of diabetes. […] Podocyte dysfunction in DKD drives proteinuria. […] Proximal tubule cell pathology correlates with GFR changes. […] Current and future mechanism-based therapies. […] In summary, functional and genetic studies highlighted the key role of podocytes in DKD, specifically in albuminuria. […] Podocyte hypertrophy might start before albuminuria, which seems to be adaptive early on but contributes to scarring later. […] In summary, PT cells play a key role in DKD development. […] Despite our remarkable therapeutic success over the last couple of years, a large number of patients continue to progress. Understanding disease-driving mechanisms provides new opportunities for precision therapeutics to treat this devastating disease condition.

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