Materiały źródłowe

• #1 Autosomal Dominant Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532934/

  Autosomal dominant polycystic kidney disease (ADPKD) involves mutations in various genes, two of which are identified. PKD1 (chromosome 16p13.3) accounts for 85% of ADPKD cases, and PKD2 (4q21) contributes 15%. […] Mutations in the PKD1 and PKD2 genes express similar phenotypes. In the PKD1 form, about 50% of patients need renal replacement therapy by 60 years. PKD2 mutations are seen in older individuals and present with a milder disease with fewer renal cysts, late-onset hypertension, and less end-stage kidney disease (ESKD) than PKD1. […] Eighty-five percent of patients with ADPKD have PKD1 mutations, 15% have the PKD2 gene mutation, and about 1% have GANAB gene mutations. Other mutations leading to PKD are unidentified, and 10% to 15% of patients with ADPKD have no known family history, suggesting a high de novo mutation rate.

• #2 Polycystic Kidney Disease: Pathogenesis and Potential Therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3139769/

  Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent, inherited condition for which there is currently no effective specific clinical therapy. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells which gradually compress the parenchyma and compromise renal function. Current interests in the field focus on understanding and exploiting signaling mechanisms underlying disease pathogenesis as well as delineating the role of the primary cilium in cystogenesis. This review highlights the pathogenetic pathways underlying renal cyst formation as well as novel therapeutic targets for the treatment of PKD. […] Autosomal dominant polycystic kidney disease is fairly common, affecting between 1 in 500 to 1 in 1,000 people. The disease is characterized by the slow development, over decades, of large fluid filled cysts in the kidneys.

• #3 Autosomal Dominant Polycystic Kidney Disease (ADPKD) – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/cystic-kidney-disease/autosomal-dominant-polycystic-kidney-disease-adpkd

  Autosomal dominant polycystic kidney disease (ADPKD) has an incidence of 1/1000 and accounts for about 5% of patients with end-stage kidney disease (ESKD) requiring renal replacement therapy. […] In most cases, ADPKD is caused by mutations in the PKD1 gene on chromosome 16, which codes for the protein polycystin 1; most other cases are caused by mutations in the PKD2 gene on chromosome 4, which codes for polycystin 2. A leading hypothesis proposes that tubular cell proliferation and differentiation are linked to flow rate and that ciliary dysfunction may thus lead to cystic transformation. […] Vasopressin promotes cell growth and fluid secretion via the cyclic AMP pathway, which leads to increase in the size and number of cysts in polycystic kidney disease. […] Early in the disorder, tubules dilate and slowly fill with glomerular filtrate. Eventually, the tubules separate from the functioning nephron and fill with secreted rather than filtered fluid, forming cysts.

• #4

  https://journals.aboutscience.eu/index.php/gcnd/article/view/2489

  Autosomal Dominant Polycystic Kidney (ADPKD) is the most common genetically determined kidney disease of Mendelian inheritance. […] It is part of the so-called ciliopathies and is mainly caused by the mutation of two genes: PKD1, located on chromosome 16p and the PKD2 gene, located on chromosome 4q and coding for Polycystin-2 (PC2); although two other disease-causing genes have recently been identified: DNAJB11 and GANAB. […] The molecular mechanisms underlying the genesis of the cysts are multiple and for this reason not yet completely understood and although several of them have been the subject of preclinical and clinical studies aimed at evaluating the efficacy of therapies that could continue to interfere in a specific way, to date, only tolvaptan and octreotide-LAR (the latter only in Italy) have been approved for the treatment of renal disease secondary to ADPKD. […] Here, we therefore recapitulate the different pathogenetic pathways in ADPKD and the possible therapeutic treatments.

• #5 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. […] The gene products of PKD1 and PKD2 genes are polycystin-1 (PC1) and polycystin-2 (PC2). PC1 and PC2 modulate number of signaling pathways in cooperation with many other proteins. Subcellularly, both proteins can be found in plasma membrane and PC2 in endoplasmic reticulum membrane. The assembly of PC1/PC2 complex obtained by cryo-electron microscopy was first presented in 2018. PC1/PC2 complex was found to be formed by one PC1 and three PC2 molecules. This observation suggests that due to three positively charged, cavity-facing residues of PC1 protein, cation permeation of the channel may be inhibited.

• #6 Polycystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/244907-overview

  Cellular proliferation and fluid secretion may be accelerated by cyclic adenosine monophosphate (cAMP) and growth factors such as epidermal growth factor (EGF). In summary, cysts function as autonomous structures and are responsible for progressive kidney enlargement in ADPKD. […] Approximately 85-90% of patients with ADPKD have an abnormality in the PKD1 gene located on the short arm of chromosome 16. Most of the remaining 10-15% of ADPKD cases are caused by pathogenic variants in the PKD2 gene, which is located on the long arm of chromosome 4. A third candidate gene, GANAB (glucosidase II alpha subunit), accounting for a very low number of ADPKD cases, has also been described. […] PKD1 and PKD2 are expressed in most organs and tissues of the human body. The proteins that are encoded by PKD1 and PKD2, polycystin 1 (PC1) and polycystin 2 (PC2), seem to function together to regulate the morphologic configuration of epithelial cells.

• #7 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  Recent evidence suggests that the primary abnormality leading to cyst formation in both the autosomal dominant and recessive forms of PKD is related to defects in cilia-mediated signaling activity. […] Specifically, PKD is thought to result from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. […] In a 2009 review of the pathogenesis of PKD, Patel et al discuss the accumulating evidence supporting the role of the primary cilium in PKD. […] They note the identification of polycystin-1, polycystin-2, and fibrocystin, the proteins associated with ADPKD and ARPKD, within the primary cilia and basal body of renal tubular epithelia, suggesting that defects in these proteins and subsequent cilia formation may lead to PKD.

• #8 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20220713/Study-uncovers-an-over-looked-mechanism-that-likely-contributes-to-autosomal-dominant-polycystic-kidney-disease.aspx

  Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic condition that can lead to kidney failure and that has no cure. Recent research published in JASN uncovers an over-looked mechanism that likely contributes to this condition. The findings provide a better understanding of ADPKD and may lead to new strategies to treat it. […] Mutations in the PKD1 gene, which codes for polycystin-1 (PC1), or the PKD2 gene, which codes for polycystin-2 (PC2), cause most cases of ADPKD. The PC1 and PC2 proteins function as receptor-channel complexes for calcium and other ions, and they’re found in cell structures called primary cilia. Primary cilia are tiny, fingerlike projections that line the small tubes where urine is formed. […] Loss of PC1 and PC2 in cilia is believed central to the pathogenesis of cyst formation that’s a hallmark of ADPKD.

• #9 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. […] The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. […] The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. […] The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. […] Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD.

• #10 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  Analysis of DNA samples extracted from individual cyst-lining epithelia of affected kidneys provided essential elements for the processes of elucidating the molecular basis of cystogenesis and explaining disease variability. […] According to this two-hit model, the germline mutation constitutes the first hit, while the second event is represented by a somatic mutation in the previously normal allele. […] The mechanism of cyst formation in ADPKD, however, has been comprehensively analyzed in recent years, improving the originally proposed two-hit model. […] These findings suggest that the biological consequences of Pkd1 inactivation are determined by a developmental switch that signals the end of the kidney maturation process. […] A subsequent study from the same group was able to prove this point, showing that renal ischemia/reperfusion (IR) can behave as a third hit for cyst formation in adult kidneys.

• #11

  https://journals.lww.com/co-nephrolhypertens/fulltext/2000/07000/the_pathogenesis_of_autosomal_dominant_polycystic.10.aspx

  The identification of PKD1 and PKD2, the two major genes responsible for autosomal dominant polycystic kidney disease, are the seminal discoveries upon which much of the current investigation into the pathogenesis of this common heritable disease is based. A major mechanistic insight was achieved with the discovery that autosomal dominant polycystic kidney disease occurs by a two-hit mechanism requiring somatic inactivation of the normal allele in individual polarized epithelial cells. […] Mounting evidence supports the hypothesis that polycystin-1 is a cell surface receptor. […] Indirect evidence also supports the initial hypothesis that polycystin-2 is a calcium channel subunit. […] Overall, the difficult task of understanding the autosomal dominant polycystic disease process is proceeding apace.

• #12 Polycystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/244907-overview

  The main feature of ADPKD is a bilateral progressive increase in the number of cysts, which may reduce kidney function to the point where the individual requires kidney replacement therapy (KRT). Hepatic cysts, intracranial aneurysms, and cardiac valvular abnormalities also may occur. […] Although ADPKD is a systemic disease, it shows a focal expression; less than 1% of nephrons become cystic. In ADPKD, each epithelial cell within a renal tubule harbors a germ-line mutation, yet only a tiny fraction of the tubules develop kidney cysts. […] It is currently held that the cells are protected by the allele inherited from the parent without ADPKD. When this allele is inactivated by a somatic event (eg, mutation) within a solitary renal tubule cell, the cell divides repeatedly until a cyst develops, with an aberrant growth program causing unchecked expansion.

• #13 Autosomal Dominant Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532934/

  Each renal cyst is believed to originate from a single, genetically transformed clonal hyperproliferative epithelial cell. A somatic mutation, known as the „second hit,” in either the PKD1 or PKD2 gene leads to cyst growth and development. The continuous proliferation of epithelial cells, fluid secretion, and alterations in the extracellular matrix result in focal outpouching from the parent nephron. […] Cyst formation can occur in proximal and distal tubules but is most common in the distal nephron and collecting duct. Cysts become separate from the parent nephron when their size exceeds 2 cm and continue to autonomously secrete fluid, leading to cyst expansion and kidney enlargement, which, in turn, results in a reduction in functional nephrons. The continuous expansion of cysts compresses renal vessels, leading to intrarenal ischemia, which activates the renin-angiotensin-aldosterone system as well as other factors.

• #14 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  Analysis of DNA samples extracted from individual cyst-lining epithelia of affected kidneys provided essential elements for the processes of elucidating the molecular basis of cystogenesis and explaining disease variability. […] According to this two-hit model, the germline mutation constitutes the first hit, while the second event is represented by a somatic mutation in the previously normal allele. […] The mechanism of cyst formation in ADPKD, however, has been comprehensively analyzed in recent years, improving the originally proposed two-hit model. […] These findings suggest that the biological consequences of Pkd1 inactivation are determined by a developmental switch that signals the end of the kidney maturation process. […] A subsequent study from the same group was able to prove this point, showing that renal ischemia/reperfusion (IR) can behave as a third hit for cyst formation in adult kidneys.

• #15

  https://www.jci.org/articles/view/72272

  Although somatic mutation may be a means to form a cyst and may be important in cyst progression, there is increasing evidence that cysts can develop with some PC present and that cyst development is a dynamic process. […] A hypothesis is now becoming accepted in which cysts develop below a specific PC threshold, with the dosage of functional PC associated with disease severity. […] Reaching this threshold may occur by a combination of one or more of the following factors: somatic mutation, variants at the ADPKD genes and beyond, stochastic expression differences between cells, and environmental factors such as renal injury. […] This period corresponds to the completion of renal development in the mouse and suggests that the timing of secondary events may influence disease severity in human ADPKD.

• #16

  https://www.jci.org/articles/view/72272

  Although somatic mutation may be a means to form a cyst and may be important in cyst progression, there is increasing evidence that cysts can develop with some PC present and that cyst development is a dynamic process. […] A hypothesis is now becoming accepted in which cysts develop below a specific PC threshold, with the dosage of functional PC associated with disease severity. […] Reaching this threshold may occur by a combination of one or more of the following factors: somatic mutation, variants at the ADPKD genes and beyond, stochastic expression differences between cells, and environmental factors such as renal injury. […] This period corresponds to the completion of renal development in the mouse and suggests that the timing of secondary events may influence disease severity in human ADPKD.

• #17

  https://journals.lww.com/cjasn/fulltext/2021/05000/insights_into_autosomal_dominant_polycystic_kidney.19.aspx

  Genetic studies from patients and animal models have informed disease pathobiology and strongly support a threshold model in which cyst formation is triggered by reduced functional polycystin dosage below a critical threshold within individual tubular epithelial cells due to (1) germline and somatic PKD1 and/or PKD2 mutations, (2) mutations of genes (e.g., SEC63, SEC61B, GANAB, PRKCSH, DNAJB11, ALG8, and ALG9) in the endoplasmic reticulum protein biosynthetic pathway, or (3) somatic mosaicism. […] The mechanisms by which reduced polycystin signaling in the primary cilia of tubular epithelial cells leads to cystic disease remain incompletely understood. Experimental therapies targeting increased cAMP, activation of the mammalian target of rapamycin complex 1 (mTORC1), and reduced 5-AMPactivated protein kinase signaling have been shown to slow cystic disease progression.

• #18

  https://www.jci.org/articles/view/64313

  Data from a handful of additional families, highlighting other possible incompletely penetrant alleles, indicate a broader applicability, but studies of larger populations and better definition of these alleles are needed to determine the full importance of in trans inheritance to explaining early-onset disease. […] Hence, it seems reasonable to propose that ADPKD severity is directly related to PC-1 dosage; adult-onset disease is usually caused by a 50% PC-1 reduction (haploinsufficiency), while further reductions due to variants on the normal allele cause severe early-onset presentations.

• #19 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  Recent evidence suggests that the primary abnormality leading to cyst formation in both the autosomal dominant and recessive forms of PKD is related to defects in cilia-mediated signaling activity. […] Specifically, PKD is thought to result from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. […] In a 2009 review of the pathogenesis of PKD, Patel et al discuss the accumulating evidence supporting the role of the primary cilium in PKD. […] They note the identification of polycystin-1, polycystin-2, and fibrocystin, the proteins associated with ADPKD and ARPKD, within the primary cilia and basal body of renal tubular epithelia, suggesting that defects in these proteins and subsequent cilia formation may lead to PKD.

• #20 Polycystic kidney disease – Wikipedia

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

  Both autosomal dominant and autosomal recessive polycystic kidney disease cyst formation are tied to abnormal cilia-mediated signaling. The polycystin-1 and polycystin-2 proteins appear to be involved in both autosomal dominant and recessive polycystic kidney disease due to defects in both proteins. […] The disease is characterized by a 'second hit’ phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic 'hit’, resulting in renal tubular cyst formation and disease progression. […] PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. […] While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Wnt/-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). Function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades which produce differentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.

• #21 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. […] The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. […] The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. […] The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. […] Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD.

• #22 Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-020-00246-3

  While the exact pathological roles of these proteins are still debated but it is clear that cystogenesis in ADPKD takes place when both the copies of either PKD 1 or PKD2 gets mutated and cause the defect in the primary cilia owing to the change in the genetic expression of aforementioned genes. […] The resulting abrupt expression (under-expression or over-expression) of polycystin-1/2 leads to the disruption of several intracellular signaling pathways that further lead to the progressive development of cyst due to dysregulation of cell proliferation and fluid secretion into the cyst. […] The primary cilia are the non-motile organelles that bulge from the apical side of the epithelial cells to the outside of the lumen of the nephron. In the kidney, they function as mechanical and chemo-sensors; translating the extracellular stimuli into the calcium ion influx through polycystin-2.

• #23 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Hedgehog, Wnt/-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). […] The role of PCP in the etiology of PKD was originally demonstrated by Fischer et al who found that PCK rats (carrying mutations in PKHD1), had randomized patterns of cell division, contributing to tubular dilation and cyst formation. […] This polarity is thought to be regulated by the primary cilium, as mice with the inactivated Kif3a gene have also been found to display disorganized cell division, suggesting disrupted PCP. […] Accordingly, with mutations in PKD1, PKD2, or PKHD1, function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades that produce dedifferentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.

• #24 Polycystic kidney disease – Wikipedia

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

  Both autosomal dominant and autosomal recessive polycystic kidney disease cyst formation are tied to abnormal cilia-mediated signaling. The polycystin-1 and polycystin-2 proteins appear to be involved in both autosomal dominant and recessive polycystic kidney disease due to defects in both proteins. […] The disease is characterized by a 'second hit’ phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic 'hit’, resulting in renal tubular cyst formation and disease progression. […] PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. […] While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Wnt/-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). Function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades which produce differentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.

• #25 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  It is currently admitted that PC2 in the ER participates in intracellular Ca2+ homeostasis. […] The fact that the polycystins participate in several cell signaling pathways makes the process of elucidating these molecular mechanisms a complex task. […] In contrast to normal kidney epithelial cells, in which cAMP inhibits proliferation, ADPKD cells present an aberrant proliferative response to cAMP. […] The disruption of PCP appears to play a role in ADPKD cyst expansion. […] The molecular basis of these abnormalities in cell division orientation has received some clues in the recent years.

• #26 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  C-terminus of PC2 interacts with IP3 receptor (IP3R) on endoplasmic reticulum and can prolong IP3-dependent calcium release. On the contrary, PC1 has an ability to inhibit this calcium release as it weakens the interaction between PC2 and IP3R. It was shown that in the cell with PC1 expression the PI3K/Akt (Phosphatidylinositol-4,5-bisphosphate 3-kinase/Protein kinase B) pathway is activated. […] Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). PC1 binds and activates JAK2 kinase that subsequently phosphorylates STAT proteins (STAT1 and 3). Phosphorylated STAT1 shifts to the nucleus to bind to p21 gene promoter which is associated with higher gene expression. Increased levels of p21 prevent cells from proliferating by arrest in G0 phase of cell cycle.

• #27 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  One of the typical features of cyst-lining cells is elevated cAMP levels. cAMP stimulates the growth of cystic cells through stimulation of protein kinase A and activation of the Ras/Raf/ERK pathway leading to proliferation and enlargement of cystic cells. Cell proliferation of extracellular matrix is also increased. Moreover, cAMP increases the fluid secretion (involving cystic fibrosis transmembrane conductance regulator-CFTR) causing cyst growth. […] The negative effect of PC1 on TSC-mTOR pathway (tuberous sclerosis complex-mammalian target of rapamycin) was described. TSC complex consisting of proteins TSC1 (also called hamartin) and TSC2 (also called tuberin) plays a role as a negative regulator of mTOR kinase, as it acts as a GTPase-activating protein. mTOR complex regulates cell growth and proliferation, as well as actin cytoskeleton and apoptosis.

• #28 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  It is currently admitted that PC2 in the ER participates in intracellular Ca2+ homeostasis. […] The fact that the polycystins participate in several cell signaling pathways makes the process of elucidating these molecular mechanisms a complex task. […] In contrast to normal kidney epithelial cells, in which cAMP inhibits proliferation, ADPKD cells present an aberrant proliferative response to cAMP. […] The disruption of PCP appears to play a role in ADPKD cyst expansion. […] The molecular basis of these abnormalities in cell division orientation has received some clues in the recent years.

• #29 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  One of the typical features of cyst-lining cells is elevated cAMP levels. cAMP stimulates the growth of cystic cells through stimulation of protein kinase A and activation of the Ras/Raf/ERK pathway leading to proliferation and enlargement of cystic cells. Cell proliferation of extracellular matrix is also increased. Moreover, cAMP increases the fluid secretion (involving cystic fibrosis transmembrane conductance regulator-CFTR) causing cyst growth. […] The negative effect of PC1 on TSC-mTOR pathway (tuberous sclerosis complex-mammalian target of rapamycin) was described. TSC complex consisting of proteins TSC1 (also called hamartin) and TSC2 (also called tuberin) plays a role as a negative regulator of mTOR kinase, as it acts as a GTPase-activating protein. mTOR complex regulates cell growth and proliferation, as well as actin cytoskeleton and apoptosis.

• #30 Autosomal dominant polycystic kidney disease: Emerging concepts of pathogenesis and new treatments | MDedge

  https://community.the-hospitalist.org/content/autosomal-dominant-polycystic-kidney-disease-emerging-concepts-pathogenesis-and-new

  Germline mutations of PKD1 or PKD2 combined with somatic mutations of the normal paired chromosome depress levels of their normal gene products (polycystin 1 and polycystin 2) to the point that cysts develop. […] The absence of polycystin permits excessive kinase activity in the mTOR pathway and the development of renal cysts. […] Research into the structure and function of the polycystin 1 and polycystin 2 proteins and what goes wrong when they are not produced in sufficient quantity or accurately is pointing the way to possible treatments for ADPKD.

• #31 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  The cytosolic domain of PC1 activates transcription factor AP-1 (activating protein-1). AP-1 influences the cellular actions such as differentiation, proliferation and apoptosis. Firstly, heterotrimeric G-proteins are activated by C-terminus of PC1. The activated Gα subunits activates c-Jun N-terminal kinase (JNK, member of MAPK kinases) that phosphorylates AP-1 transcription factor. […] The Wnt signaling pathway regulates essential biological functions. Wnt proteins are growth factors. They play a roles in signaling pathways controlling proliferation, differentiation and cellular polarity during embryonal development. In canonical Wnt pathway, secreted glycoproteins Wnt bind to Frizzled receptor (containing co-receptor LRP-low-density lipoprotein receptor-related protein).

• #32 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  These signaling pathways have been found to include cAMP-activated, Wnt signaling, and mammalian target of rapamycin (mTOR) pathways, the discoveries of which have greatly expanded the number of potential therapeutic targets for the disease. […] Ultimately, cyst growth and expansion compresses renal vessels and leads to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS), in turn producing progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis. […] Vascular manifestations of ADPKD are thought to also be related to abnormal functioning of polycystin-1 and polycystin-2, which additionally have been found to be expressed in vascular smooth muscle and endothelium. […] When this mechanosensory function is lost in ADPKD, calcium signaling is disrupted, contributing to cyst formation and numerous vascular alterations. […] Additional work has revealed that a reduced dose of PKD1 in mouse models is associated with vascular dysfunction, resulting in age-dependent increases in vascular reactivity.

• #33 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  C-terminus of PC2 interacts with IP3 receptor (IP3R) on endoplasmic reticulum and can prolong IP3-dependent calcium release. On the contrary, PC1 has an ability to inhibit this calcium release as it weakens the interaction between PC2 and IP3R. It was shown that in the cell with PC1 expression the PI3K/Akt (Phosphatidylinositol-4,5-bisphosphate 3-kinase/Protein kinase B) pathway is activated. […] Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). PC1 binds and activates JAK2 kinase that subsequently phosphorylates STAT proteins (STAT1 and 3). Phosphorylated STAT1 shifts to the nucleus to bind to p21 gene promoter which is associated with higher gene expression. Increased levels of p21 prevent cells from proliferating by arrest in G0 phase of cell cycle.

• #34 Polycystic Kidney Disease: Pathogenesis and Potential Therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3139769/

  Amongst ADPKD patients, 85-90% of cases result from mutations in PKD1, while another 10-15% of cases are accounted for by mutations in PKD2. […] While the exact physiological and pathological roles of these two proteins are still debated, it is clear that renal cystogenesis occurs when both copies of one or the other polycystin gene are either mutated or knocked out. […] The pathological processes that facilitate cyst enlargement, however, are hypothesized to result from two specific cellular abnormalities: 1) increased fluid secretion into the cyst lumen and 2) inappropriately increased cell division of the cyst lining epithelium. […] Recent advances in the understanding of pathways governing renal cystogenesis have led to a number of intriguing possibilities for therapeutic intervention. […] At present, there are no FDA-approved therapies for the treatment of PKD, and patients who progress to end-stage renal disease require renal replacement therapy.

• #35

  https://link.springer.com/article/10.1007/s10157-012-0741-0

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common progressive hereditary kidney disease. In 8590 % of cases, ADPKD results from a mutation in the PKD1 gene, and the other 1015 % of the cases are accounted for by mutations in PKD2. PKD1 and PKD2 encode polycystin-1 and polycystin-2. Polycystin-1 may be a receptor that controls the channel activity of polycystin-2 as part of the polycystin signaling complex. ADPKD is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that gradually compress the parenchyma and compromise renal function. […] The pathological processes that facilitate cyst enlargement are hypothesized to result from two specific cellular abnormalities: (1) increased fluid secretion into the cyst lumen and (2) inappropriately increased cell division by the epithelium lining the cyst.

• #36 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  It is currently admitted that PC2 in the ER participates in intracellular Ca2+ homeostasis. […] The fact that the polycystins participate in several cell signaling pathways makes the process of elucidating these molecular mechanisms a complex task. […] In contrast to normal kidney epithelial cells, in which cAMP inhibits proliferation, ADPKD cells present an aberrant proliferative response to cAMP. […] The disruption of PCP appears to play a role in ADPKD cyst expansion. […] The molecular basis of these abnormalities in cell division orientation has received some clues in the recent years.

• #37 Autosomal dominant polycystic kidney disease | Nefrología

  https://revistanefrologia.com/en-autosomal-dominant-polycystic-kidney-disease-articulo-X0211699503028673

  The cyst-derived epithelial cells are characterized by a partially dedifferentiated phenotype and an abnormal proliferative response to cyclic AMP agonists that normally inhibit proliferation in the renal tubular epithelial cells. […] When the cysts reach ~2 mm in diameter, they become disconnected from the tubules. […] Accumulation of fluid within these cysts occurs by chloride driven fluid secretion which is also stimulated by cyclic AMP. […] Compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells are the causative mechanisms.

• #38 Autosomal dominant polycystic kidney disease – Wikipedia

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

  Epithelial cell proliferation and fluid secretion that lead to cystogenesis are two hallmark features in ADPKD. During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts. Once these cysts expand to approximately 2mm in diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased intracellular concentration of cyclic AMP (cAMP).

• #39 Autosomal dominant polycystic kidney disease | Nefrología

  https://revistanefrologia.com/en-autosomal-dominant-polycystic-kidney-disease-articulo-X0211699503028673

  The cyst-derived epithelial cells are characterized by a partially dedifferentiated phenotype and an abnormal proliferative response to cyclic AMP agonists that normally inhibit proliferation in the renal tubular epithelial cells. […] When the cysts reach ~2 mm in diameter, they become disconnected from the tubules. […] Accumulation of fluid within these cysts occurs by chloride driven fluid secretion which is also stimulated by cyclic AMP. […] Compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells are the causative mechanisms.

• #40 Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-020-00246-3

  The key characteristic of ADPKD is the development of a large number of the fluid-filled cyst, which is mainly based on CFTR. […] The activation of PPAR-gamma leads to various actions that consequently leads to the actions that include transactivation of the genes that regulate the adipocyte differentiation that leads to an increased number of small insulin-sensitive adipocytes, increased uptake of glucose by skeletal muscle, and decreased production of glucose by the liver which consequently are responsible for its glucose-lowering effect in type-2 diabetes mellitus patients; thereby decreasing the insulin resistance. […] Through PPAR- activation, pioglitazone exerts beneficial actions in ADPKD, which is discussed in the next section. […] The efficacy in preclinical studies has made it an efficient drug for ADPKD treatment.

• #41 Autosomal Dominant Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532934/

  Hypertension in ADPKD is postulated to be related to local areas of kidney ischemia, which develop due to cyst expansion. This results in increased renin release and a rise in blood pressure. […] The cysts also trigger an inflammatory response in the surrounding renal parenchyma and promote renal fibrosis. Progressive cyst expansion, greater systemic vascular resistance, sodium retention, and increasing renal fibrosis ultimately lead to ESKD.

• #42 Polycystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/244907-overview

  The severity of ADPKD is thought to be a direct consequence of the number of times and the frequency with which this cystogenic process occurs within the kidneys over the life of the patient. […] The hyperplastic cells cause an out-pocketing of the tubule wall, with the formation of a saccular cyst that fills with fluid derived from glomerular filtrate that enters from the afferent tubule segment. Progressive expansion eventually causes most of the emerging cysts to separate from the parent tubule, leaving an isolated sac that fills with fluid by transepithelial secretion. This isolated cyst expands relentlessly as a result of continued proliferation of the mural epithelium together with the transepithelial secretion of sodium chloride and water into the lumen. […] The expanding fluid-filled tumor masses elicit secondary and tertiary changes within the renal interstitium evinced by thickening and lamination of the tubule basement membranes, infiltration of macrophages, and neovascularization. Fibrosis within the interstitium begins early in the course of the disease.

• #43 Polycystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/244907-overview

  The severity of ADPKD is thought to be a direct consequence of the number of times and the frequency with which this cystogenic process occurs within the kidneys over the life of the patient. […] The hyperplastic cells cause an out-pocketing of the tubule wall, with the formation of a saccular cyst that fills with fluid derived from glomerular filtrate that enters from the afferent tubule segment. Progressive expansion eventually causes most of the emerging cysts to separate from the parent tubule, leaving an isolated sac that fills with fluid by transepithelial secretion. This isolated cyst expands relentlessly as a result of continued proliferation of the mural epithelium together with the transepithelial secretion of sodium chloride and water into the lumen. […] The expanding fluid-filled tumor masses elicit secondary and tertiary changes within the renal interstitium evinced by thickening and lamination of the tubule basement membranes, infiltration of macrophages, and neovascularization. Fibrosis within the interstitium begins early in the course of the disease.

• #44 Autosomal Dominant Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532934/

  Each renal cyst is believed to originate from a single, genetically transformed clonal hyperproliferative epithelial cell. A somatic mutation, known as the „second hit,” in either the PKD1 or PKD2 gene leads to cyst growth and development. The continuous proliferation of epithelial cells, fluid secretion, and alterations in the extracellular matrix result in focal outpouching from the parent nephron. […] Cyst formation can occur in proximal and distal tubules but is most common in the distal nephron and collecting duct. Cysts become separate from the parent nephron when their size exceeds 2 cm and continue to autonomously secrete fluid, leading to cyst expansion and kidney enlargement, which, in turn, results in a reduction in functional nephrons. The continuous expansion of cysts compresses renal vessels, leading to intrarenal ischemia, which activates the renin-angiotensin-aldosterone system as well as other factors.

• #45 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  These signaling pathways have been found to include cAMP-activated, Wnt signaling, and mammalian target of rapamycin (mTOR) pathways, the discoveries of which have greatly expanded the number of potential therapeutic targets for the disease. […] Ultimately, cyst growth and expansion compresses renal vessels and leads to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS), in turn producing progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis. […] Vascular manifestations of ADPKD are thought to also be related to abnormal functioning of polycystin-1 and polycystin-2, which additionally have been found to be expressed in vascular smooth muscle and endothelium. […] When this mechanosensory function is lost in ADPKD, calcium signaling is disrupted, contributing to cyst formation and numerous vascular alterations. […] Additional work has revealed that a reduced dose of PKD1 in mouse models is associated with vascular dysfunction, resulting in age-dependent increases in vascular reactivity.

• #46 Autosomal Dominant Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532934/

  Hypertension in ADPKD is postulated to be related to local areas of kidney ischemia, which develop due to cyst expansion. This results in increased renin release and a rise in blood pressure. […] The cysts also trigger an inflammatory response in the surrounding renal parenchyma and promote renal fibrosis. Progressive cyst expansion, greater systemic vascular resistance, sodium retention, and increasing renal fibrosis ultimately lead to ESKD.

• #47 Autosomal dominant polycystic kidney disease and the heart and brain | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/84/6/471

  Autosomal dominant polycystic kidney disease (ADPKD) has numerous systemic manifestations and complications. This article gives an overview of hypertension, cardiac complications, and intracranial aneurysms in ADPKD, their pathophysiology, and recent developments in their management. […] Hypertension in ADPKD is multifactorial. The major factors associated with its development are increased activation of the renin-angiotensin-aldosterone system (RAAS); overexpression of endothelin receptor subtype A (ET-A) in cystic kidneys; increased production of endothelin 1 (ET-1); and sodium retention. […] Activation of the RAAS plays a major role in the development and maintenance of hypertension in ADPKD. This is thought to be mainly due to progressive enlargement of renal cysts, which causes renal arteriolar attenuation and ischemia secondary to pressure effects, which in turn activates the RAAS.

• #48 Autosomal Dominant Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532934/

  Hypertension in ADPKD is postulated to be related to local areas of kidney ischemia, which develop due to cyst expansion. This results in increased renin release and a rise in blood pressure. […] The cysts also trigger an inflammatory response in the surrounding renal parenchyma and promote renal fibrosis. Progressive cyst expansion, greater systemic vascular resistance, sodium retention, and increasing renal fibrosis ultimately lead to ESKD.

• #49 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  These signaling pathways have been found to include cAMP-activated, Wnt signaling, and mammalian target of rapamycin (mTOR) pathways, the discoveries of which have greatly expanded the number of potential therapeutic targets for the disease. […] Ultimately, cyst growth and expansion compresses renal vessels and leads to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS), in turn producing progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis. […] Vascular manifestations of ADPKD are thought to also be related to abnormal functioning of polycystin-1 and polycystin-2, which additionally have been found to be expressed in vascular smooth muscle and endothelium. […] When this mechanosensory function is lost in ADPKD, calcium signaling is disrupted, contributing to cyst formation and numerous vascular alterations. […] Additional work has revealed that a reduced dose of PKD1 in mouse models is associated with vascular dysfunction, resulting in age-dependent increases in vascular reactivity.

• #50 Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy | Pediatric Research

  https://www.nature.com/articles/pr2013191

  Abnormal structure and/or function of the primary cilia; […] Alterations in planar cell polarity; […] Alterations in cell-cell and cell-matrix interactions. […] The first three of the phenotypic features noted above are clearly mechanistic, whereas the others appear to be associative. […] Given the complex intracellular cascades activated in both ADPKD and ARPKD, the holy grail of future therapy is to identify key cellular checkpoints where diffuse processes responsible for the cystic phenotype are integrated. […] cSrc (pp66Src) is a key focal intermediate in several central cystogenic signaling pathways. […] Increased Src in PKD uncouples EGFR ligands from peritubular matrix, reciprocally phosphorylates EGFR, and is required for the phosphorylation of -Raf, allowing a normal inhibitory mechanism and preventing renal epithelial proliferation to be bypassed.

• #51 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. […] The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. […] The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. […] The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. […] Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD.

• #52 Autosomal dominant polycystic kidney disease | Nefrología

  https://revistanefrologia.com/en-autosomal-dominant-polycystic-kidney-disease-articulo-X0211699503028673

  The cyst-derived epithelial cells are characterized by a partially dedifferentiated phenotype and an abnormal proliferative response to cyclic AMP agonists that normally inhibit proliferation in the renal tubular epithelial cells. […] When the cysts reach ~2 mm in diameter, they become disconnected from the tubules. […] Accumulation of fluid within these cysts occurs by chloride driven fluid secretion which is also stimulated by cyclic AMP. […] Compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells are the causative mechanisms.

• #53 Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy | Pediatric Research

  https://www.nature.com/articles/pr2013191

  Cyst initiation and expansion is a complex process characterized by abnormalities in tubular cell proliferation, fluid secretion, extracellular matrix formation, and cell polarity of specific proteins. […] Despite the lack of understanding of the precise molecular mechanisms by which mutations in PKD1, PKD2, and PKHD1 result in renal cyst formation, a number of common phenotypic abnormalities have been identified. […] The unique cystic phenotype is characterized by quantitative and qualitative abnormalities in expression and function of the epidermal growth factor (EGF) family of receptors and ligands (EGF receptor (EGFR) axis); […] Aberrant adenosine 3,5-cyclic monophosphate (cAMP) signaling, resulting in proliferation and decreased intracellular calcium; […] Abnormal activity of C-terminal Src kinase or cellular Src (cSrc);

• #54 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Hedgehog, Wnt/-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). […] The role of PCP in the etiology of PKD was originally demonstrated by Fischer et al who found that PCK rats (carrying mutations in PKHD1), had randomized patterns of cell division, contributing to tubular dilation and cyst formation. […] This polarity is thought to be regulated by the primary cilium, as mice with the inactivated Kif3a gene have also been found to display disorganized cell division, suggesting disrupted PCP. […] Accordingly, with mutations in PKD1, PKD2, or PKHD1, function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades that produce dedifferentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.

• #55 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  It is currently admitted that PC2 in the ER participates in intracellular Ca2+ homeostasis. […] The fact that the polycystins participate in several cell signaling pathways makes the process of elucidating these molecular mechanisms a complex task. […] In contrast to normal kidney epithelial cells, in which cAMP inhibits proliferation, ADPKD cells present an aberrant proliferative response to cAMP. […] The disruption of PCP appears to play a role in ADPKD cyst expansion. […] The molecular basis of these abnormalities in cell division orientation has received some clues in the recent years.

• #56 Cross-Species Insights into Autosomal Dominant Polycystic Kidney Disease: Provide an Alternative View on Research Advancement

  https://www.mdpi.com/1422-0067/25/11/5646

  Nevertheless, several signaling pathways are implicated in its pathogenesis, consisting of the HIF-1α, mTOR, TSC-1/2 complex, Wnt, JAK/STAT, AMPK, and PPAR-γ pathways. […] In addition, the dysregulation of Ca2+ channels and cAMP signaling has been observed as contributing to the accelerated proliferation of cystic epithelial cells. […] In vitro data and animal models of non-human origin have demonstrated a reduction in autophagy flux in ADPKD. […] Furthermore, current studies indicate that metabolic disorientation emerges as a pivotal characteristic of ADPKD, with affected individuals predisposed to aberrant metabolic reactions or accumulation of metabolites, exacerbating disease progression.

• #57 Cross-Species Insights into Autosomal Dominant Polycystic Kidney Disease: Provide an Alternative View on Research Advancement

  https://www.mdpi.com/1422-0067/25/11/5646

  Nevertheless, several signaling pathways are implicated in its pathogenesis, consisting of the HIF-1α, mTOR, TSC-1/2 complex, Wnt, JAK/STAT, AMPK, and PPAR-γ pathways. […] In addition, the dysregulation of Ca2+ channels and cAMP signaling has been observed as contributing to the accelerated proliferation of cystic epithelial cells. […] In vitro data and animal models of non-human origin have demonstrated a reduction in autophagy flux in ADPKD. […] Furthermore, current studies indicate that metabolic disorientation emerges as a pivotal characteristic of ADPKD, with affected individuals predisposed to aberrant metabolic reactions or accumulation of metabolites, exacerbating disease progression.

• #58 Cross-Species Insights into Autosomal Dominant Polycystic Kidney Disease: Provide an Alternative View on Research Advancement

  https://www.mdpi.com/1422-0067/25/11/5646

  Nevertheless, several signaling pathways are implicated in its pathogenesis, consisting of the HIF-1α, mTOR, TSC-1/2 complex, Wnt, JAK/STAT, AMPK, and PPAR-γ pathways. […] In addition, the dysregulation of Ca2+ channels and cAMP signaling has been observed as contributing to the accelerated proliferation of cystic epithelial cells. […] In vitro data and animal models of non-human origin have demonstrated a reduction in autophagy flux in ADPKD. […] Furthermore, current studies indicate that metabolic disorientation emerges as a pivotal characteristic of ADPKD, with affected individuals predisposed to aberrant metabolic reactions or accumulation of metabolites, exacerbating disease progression.

• #59 Tolvaptan for Autosomal Dominant Polycystic Kidney Disease | DHPS

  https://www.dovepress.com/clinical-utility-and-tolerability-of-tolvaptan-in-the-treatment-of-aut-peer-reviewed-fulltext-article-DHPS

  Tolvaptan is a selective vasopressin V2 receptor antagonist. It acts by inhibiting vasopressin from binding to the V2 receptor, thus causing aquaresis (loss of electrolyte-free water). […] According to two largest clinical trials, namely tolvaptan TEMPO 2:4 and tolvaptan TEMPO 3:4, this is the spectrum of side effects seen most in ADPKD patients who have been put on tolvaptan therapy. […] Many new treatment approaches are emerging and trying to target different aspects of the disease. Of these emergent approaches, Micheal J. Caplan discussed the importance of the enzyme adenosine monophosphate protein kinase (AMPK) in cellular metabolism and its role in ADPKD. AMPK usually acts by increasing the production mechanism of ATP when AMP levels are high and ATP levels are low. […] Thus, the new drug being researched acts on AMPK either directly (through a chemical compound that mimics AMP) or indirectly (caloric restriction which will increase the need for high energy levels) activating it to counteract the cyst generating factors in ADPKD.

• #60 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20220713/Study-uncovers-an-over-looked-mechanism-that-likely-contributes-to-autosomal-dominant-polycystic-kidney-disease.aspx

  Current dogma of ADPKD is that it is a disease in which defects primarily originate in the cilia. We demonstrate that defects in the ER perhaps play a more important role. Furthermore, the function of PC2 in the ER is to regulate potassium movement to affect calcium balance indirectly. […] In addition to providing these insights, the research suggests that activating TricB may be a promising treatment strategy for ADPKD.

• #61 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20220713/Study-uncovers-an-over-looked-mechanism-that-likely-contributes-to-autosomal-dominant-polycystic-kidney-disease.aspx

  Current dogma of ADPKD is that it is a disease in which defects primarily originate in the cilia. We demonstrate that defects in the ER perhaps play a more important role. Furthermore, the function of PC2 in the ER is to regulate potassium movement to affect calcium balance indirectly. […] In addition to providing these insights, the research suggests that activating TricB may be a promising treatment strategy for ADPKD.

• #62 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20220713/Study-uncovers-an-over-looked-mechanism-that-likely-contributes-to-autosomal-dominant-polycystic-kidney-disease.aspx

  Current dogma of ADPKD is that it is a disease in which defects primarily originate in the cilia. We demonstrate that defects in the ER perhaps play a more important role. Furthermore, the function of PC2 in the ER is to regulate potassium movement to affect calcium balance indirectly. […] In addition to providing these insights, the research suggests that activating TricB may be a promising treatment strategy for ADPKD.

• #63

  https://journals.lww.com/cjasn/fulltext/2021/05000/insights_into_autosomal_dominant_polycystic_kidney.19.aspx

  Recent genetic studies have identified a novel mechanism by which mutations in multiple genes encoding proteins functioning in the endoplasmic reticulum (ER) protein biosynthetic pathway cause ADPLD by modulating polycystin-1 dosage. Specifically, translocation proteins encoded by SEC63 and SEC61B are required for entry of nascent proteins into the ER, whereas the proteins encoded by ALG8, ALG9, and PMM2 are required in the ER for N-glycosylation of nascent proteins. […] However, the exact molecular mechanisms underlying cyst growth and disease progression remain incomplete.

• #64

  https://www.jci.org/articles/view/72272

  Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. […] Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. […] In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. […] Dominant inheritance, the focal nature of cyst development, loss/mutation of the normal allele of the affected ADPKD gene in cystic cells, and a hypermutable Pkd2 model (WS25), suggest a two-hit hypothesis of cystogenesis.

• #65

  https://www.jci.org/articles/view/72272

  Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. […] Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. […] In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. […] Dominant inheritance, the focal nature of cyst development, loss/mutation of the normal allele of the affected ADPKD gene in cystic cells, and a hypermutable Pkd2 model (WS25), suggest a two-hit hypothesis of cystogenesis.

• #66 Polycystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/244907-overview

  The severity of ADPKD is thought to be a direct consequence of the number of times and the frequency with which this cystogenic process occurs within the kidneys over the life of the patient. […] The hyperplastic cells cause an out-pocketing of the tubule wall, with the formation of a saccular cyst that fills with fluid derived from glomerular filtrate that enters from the afferent tubule segment. Progressive expansion eventually causes most of the emerging cysts to separate from the parent tubule, leaving an isolated sac that fills with fluid by transepithelial secretion. This isolated cyst expands relentlessly as a result of continued proliferation of the mural epithelium together with the transepithelial secretion of sodium chloride and water into the lumen. […] The expanding fluid-filled tumor masses elicit secondary and tertiary changes within the renal interstitium evinced by thickening and lamination of the tubule basement membranes, infiltration of macrophages, and neovascularization. Fibrosis within the interstitium begins early in the course of the disease.

• #67 Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

  https://www.mdpi.com/1422-0067/23/6/3317

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. […] The gene products of PKD1 and PKD2 genes are polycystin-1 (PC1) and polycystin-2 (PC2). PC1 and PC2 modulate number of signaling pathways in cooperation with many other proteins. Subcellularly, both proteins can be found in plasma membrane and PC2 in endoplasmic reticulum membrane. The assembly of PC1/PC2 complex obtained by cryo-electron microscopy was first presented in 2018. PC1/PC2 complex was found to be formed by one PC1 and three PC2 molecules. This observation suggests that due to three positively charged, cavity-facing residues of PC1 protein, cation permeation of the channel may be inhibited.

• #68 Polycystic Kidney Disease: Pathogenesis and Potential Therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3139769/

  Amongst ADPKD patients, 85-90% of cases result from mutations in PKD1, while another 10-15% of cases are accounted for by mutations in PKD2. […] While the exact physiological and pathological roles of these two proteins are still debated, it is clear that renal cystogenesis occurs when both copies of one or the other polycystin gene are either mutated or knocked out. […] The pathological processes that facilitate cyst enlargement, however, are hypothesized to result from two specific cellular abnormalities: 1) increased fluid secretion into the cyst lumen and 2) inappropriately increased cell division of the cyst lining epithelium. […] Recent advances in the understanding of pathways governing renal cystogenesis have led to a number of intriguing possibilities for therapeutic intervention. […] At present, there are no FDA-approved therapies for the treatment of PKD, and patients who progress to end-stage renal disease require renal replacement therapy.

• #69

  https://link.springer.com/article/10.1007/s10157-012-0741-0

  Recent advances in our understanding of the pathways that govern renal cystogenesis have led to a number of intriguing possibilities in regard to therapeutic interventions. The purpose of this article is to review the pathogenesis of renal cyst formation and to review novel targets for the treatment of ADPKD.

• #70 Autosomal Dominant Polycystic Kidney Disease (ADPKD) – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/cystic-kidney-disease/autosomal-dominant-polycystic-kidney-disease-adpkd

  Autosomal dominant polycystic kidney disease (ADPKD) has an incidence of 1/1000 and accounts for about 5% of patients with end-stage kidney disease (ESKD) requiring renal replacement therapy. […] In most cases, ADPKD is caused by mutations in the PKD1 gene on chromosome 16, which codes for the protein polycystin 1; most other cases are caused by mutations in the PKD2 gene on chromosome 4, which codes for polycystin 2. A leading hypothesis proposes that tubular cell proliferation and differentiation are linked to flow rate and that ciliary dysfunction may thus lead to cystic transformation. […] Vasopressin promotes cell growth and fluid secretion via the cyclic AMP pathway, which leads to increase in the size and number of cysts in polycystic kidney disease. […] Early in the disorder, tubules dilate and slowly fill with glomerular filtrate. Eventually, the tubules separate from the functioning nephron and fill with secreted rather than filtered fluid, forming cysts.

• #71 Tolvaptan for Autosomal Dominant Polycystic Kidney Disease | DHPS

  https://www.dovepress.com/clinical-utility-and-tolerability-of-tolvaptan-in-the-treatment-of-aut-peer-reviewed-fulltext-article-DHPS

  V2 receptor antagonism by tolvaptan in the renal collecting ducts causes a variety of physiological changes, which impact the pathophysiology of the ADPKD. It causes free water excretion resulting in net body fluid loss, increases Na+ concentration in the serum and decreases urine osmolality. Furthermore, V2 antagonism decreases cAMP which decreases cyst proliferation and helps to slow down the progression of ADPKD. […] The safety and efficacy of tolvaptan has been studied in the two largest clinical trials done on patients with ADPKD: TEMPO3:4 and REPRISE. Both showed a reduction in the decline of kidney function compared to placebo. […] The use of tolvaptan has been shown to cause several adverse side effects. Various reports have documented their incidence in patients after treatment initiation for autosomal dominant autosomal polycystic kidney disease (ADPKD).

• #72

  https://kidneys.zaslavsky.com.ua/index.php/journal/article/view/177

  Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by progressive growth of the cyst and an increase in the total volume of the kidneys which leads to kidney failure. The main causes of ADPKD are mutations in the genes PKD1 and PKD2 which encode the formation of polycystin-1 and polycystin-2 proteins. […] There is a connection between structural and functional defects in the primary cilia with the ADPKD. […] The most promising drugs for the treatment of ADPKD today are vasopressin-2 receptor antagonists, m-TOR and c-AMP inhibitors.

• #73 Tolvaptan for Autosomal Dominant Polycystic Kidney Disease | DHPS

  https://www.dovepress.com/clinical-utility-and-tolerability-of-tolvaptan-in-the-treatment-of-aut-peer-reviewed-fulltext-article-DHPS

  Tolvaptan is a selective vasopressin V2 receptor antagonist. It acts by inhibiting vasopressin from binding to the V2 receptor, thus causing aquaresis (loss of electrolyte-free water). […] According to two largest clinical trials, namely tolvaptan TEMPO 2:4 and tolvaptan TEMPO 3:4, this is the spectrum of side effects seen most in ADPKD patients who have been put on tolvaptan therapy. […] Many new treatment approaches are emerging and trying to target different aspects of the disease. Of these emergent approaches, Micheal J. Caplan discussed the importance of the enzyme adenosine monophosphate protein kinase (AMPK) in cellular metabolism and its role in ADPKD. AMPK usually acts by increasing the production mechanism of ATP when AMP levels are high and ATP levels are low. […] Thus, the new drug being researched acts on AMPK either directly (through a chemical compound that mimics AMP) or indirectly (caloric restriction which will increase the need for high energy levels) activating it to counteract the cyst generating factors in ADPKD.

• #74 Novartis Drops up to $1.7B to Bolster Oligo Pipeline With Regulus Buy – BioSpace

  https://www.biospace.com/business/novartis-drops-up-to-1-7b-to-bolster-oligo-pipeline-with-regulus-buy

  At the heart of the acquisition is Regulus farabursen, an miRNA-targeting oligonucleotide in early-stage development for rare autosomal dominant polycystic kidney disease. […] The centerpiece of Wednesdays merger is Regulus farabursenits regulatory approval is the trigger for Novartis contingent value right offeran oligonucleotide being developed for autosomal dominant polycystic kidney disease (ADPKD), a rare, hereditary condition that affects around 160,000 patients in the U.S., according to Regulus. […] The disease is caused by mutations in the Pkd1 or Pkd2 gene, leading to the accumulation of fluid-filled cysts in and across the kidneys and worsening kidney function over time. When left unchecked, ADPKD can lead to kidney failure and eventually death. […] According to Regulus, Pkd1 or Pkd2 mutations are tied to the upregulation of miR-17, a microRNA molecule that directly leads to suppression of certain genes, ultimately dampening the production of the proteins encoded by those genes, polycystin 1 (PC1) and 2 (PC2). […] Farabursen binds to miR-17 to disrupt this pathway to correct the underlying pathology of ADPKD, according to Regulus. Through this mechanism of action, farabursen can restore PC1 and PC2 levels, in turn reducing the growth of cysts.

• #75

  https://journals.aboutscience.eu/index.php/gcnd/article/view/2489

  Autosomal Dominant Polycystic Kidney (ADPKD) is the most common genetically determined kidney disease of Mendelian inheritance. […] It is part of the so-called ciliopathies and is mainly caused by the mutation of two genes: PKD1, located on chromosome 16p and the PKD2 gene, located on chromosome 4q and coding for Polycystin-2 (PC2); although two other disease-causing genes have recently been identified: DNAJB11 and GANAB. […] The molecular mechanisms underlying the genesis of the cysts are multiple and for this reason not yet completely understood and although several of them have been the subject of preclinical and clinical studies aimed at evaluating the efficacy of therapies that could continue to interfere in a specific way, to date, only tolvaptan and octreotide-LAR (the latter only in Italy) have been approved for the treatment of renal disease secondary to ADPKD. […] Here, we therefore recapitulate the different pathogenetic pathways in ADPKD and the possible therapeutic treatments.

• #76

  https://www.nhs.uk/conditions/autosomal-dominant-polycystic-kidney-disease-adpkd/

  Autosomal dominant polycystic kidney disease (ADPKD) is caused by a genetic fault that disrupts the normal development of some of the cells in the kidneys and causes cysts to grow. […] Faults in 1 of 2 different genes are known to cause ADPKD. […] The affected genes are: PKD1, which accounts for around 78% of cases; PKD2, which accounts for around 15% of cases. […] Both types of ADPKD have the same symptoms, but they tend to be more severe in PKD1. […] A child has a 1 in 2 (50%) chance of developing ADPKD if one of their parents has the faulty PKD1 or PKD2 gene. […] In around 1 in 10 cases of ADPKD, the mutation develops for the first time in the affected person. It’s not known what causes this to happen. […] A medication called tolvaptan can be used to slow down the formation of cysts and protect kidney function.

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