Materiały źródłowe

• #1

  https://omim.org/entry/173900

  Germino (1998) indicated that approximately 50% of polycystic kidney disease leads to ESRD and that 4 to 5% of ESRD is due to PKD. […] Chapman et al. (1990) reported that the renin-angiotensin-aldosterone system is stimulated significantly more in hypertensive patients with polycystic kidney disease than in comparable patients with essential hypertension. […] Reeders (1992) put forward an interesting 2-hit mutational hypothesis for PKD1. […] The hypothesis suggests that at the sites of cyst formation, a somatic mutation occurs in the chromosome 16 that does not carry the inherited mutation. […] Wilson et al. (1991) found evidence of reversed polarity of sodium-potassium-ATPase in renal tubule cells lining the cysts in this disorder. […] Ye and Grantham (1993) studied in vitro intact cysts that were excised from kidneys removed from patients with end-stage polycystic kidney disease.

• #2

  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.

• #3

  https://omim.org/entry/173900

  A number sign (#) is used with this entry because of evidence that autosomal dominant polycystic kidney disease-1 with or without polycystic liver disease (PKD1) is caused by heterozygous mutation in the PKD1 gene (601313) on chromosome 16p13. […] PKD1, an autosomal dominant form of polycystic kidney disease (ADPKD), has the cardinal manifestations of renal cysts, liver cysts, and intracranial aneurysm. […] The most serious renal complication is end-stage renal disease, which occurs in approximately 50% of patients by the age of 60 years. […] The phenotypic variability in PKD1 involves differences in the rate of loss of glomerular filtration, the age of reaching end-stage renal disease (ESRD), and the occurrence of hypertension, symptomatic extrarenal cysts, and subarachnoid hemorrhage from intracranial 'berry’ aneurysm.

• #4 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. […] 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.

• #5 Polycystic kidney disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/polycystic-kidney-disease/

  Polycystic kidney disease is a disorder that affects the kidneys and other organs. Clusters of fluid-filled sacs, called cysts, develop in the kidneys and interfere with their ability to filter waste products from the blood. The growth of cysts causes the kidneys to become enlarged and can lead to kidney failure. Cysts may also develop in other organs, particularly the liver. […] Mutations in the PKD1, PKD2, and PKHD1 genes cause polycystic kidney disease. […] Mutations in either the PKD1 or PKD2 gene can cause autosomal dominant polycystic kidney disease; PKD1 gene mutations cause ADPKD type 1, and PKD2 gene mutations cause ADPKD type 2. These genes provide instructions for making proteins whose functions are not fully understood. Researchers believe that they are involved in transmitting chemical signals from outside the cell to the cell’s nucleus. The two proteins work together to promote normal kidney development, organization, and function. Mutations in the PKD1 or PKD2 gene lead to the formation of thousands of cysts, which disrupt the normal functions of the kidneys and other organs.

• #6 Autosomal recessive polycystic kidney disease in children – UpToDate

  https://www.uptodate.com/contents/autosomal-recessive-polycystic-kidney-disease-in-children

  Autosomal recessive polycystic kidney disease (ARPKD, MIM #263200), previously called infantile polycystic kidney disease, is a recessively inherited disorder characterized by cystic dilations of the renal collecting ducts and developmental defects of hepatobiliary ductal plate remodeling, which result in varying degrees of congenital hepatic fibrosis. […] Most cases of ARPKD are caused by variants in PKHD1 (polycystic kidney and hepatic disease 1 gene) located on chromosome 6p21, which encodes fibrocystin (also referred to as polyductin), a large integral membrane protein. […] Although the function of fibrocystin is unknown, it is found in the cortical and medullary collecting ducts and the thick ascending limb of the kidney, and in the epithelial cells of the hepatic bile duct. […] This suggests that defects in fibrocystin disrupt normal functioning of renal cilia, pointing toward a shared pathogenesis of cyst formation in the two disorders.

• #7

  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.

• #8 Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3108786/

  In response to fluid flow over the renal epithelium, the primary cilium is bent, resulting in a flow-induced increase in intracellular calcium. […] 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. […] 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. […] 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.

• #9 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  In contrast, enlarging cysts lose their connection to functioning nephrons as they reach a size of more than 2 to 3 mm. […] Cyst growth in this setting results from secretion of fluid into the cysts (not glomerular filtration) and is associated with hyperplasia of the cyst epithelium that may reflect underlying maturational arrest. […] A notable feature of ADPKD is variable phenotypic disease expression. […] This observation led to a „second-hit” hypothesis of cystogenesis for both PKD1 and PKD2. […] Under the „second hit” hypothesis, cysts form in the presence of an inherited PKD1 or PKD2 mutation only if the remaining normal copy of PKD1 or PKD2 develops a somatic (acquired not inherited) mutation. […] The low detection rate of somatic mutation, however, was likely due to the challenges of performing mutation screening in the duplicated region of PKD1.

• #10

  https://link.springer.com/article/10.1007/s004390000347

  Mutations in three different genes, PKD1, PKD2 and PKD3, can cause a very similar clinical picture of the autosomal dominant form of polycystic kidney disease (ADPKD). […] Although ADPKD is a frequent monogenic disorder affecting approximately 1:1000 individuals in the Caucasian population, progress in understanding its pathology was somewhat slow until relatively recently when the PKD1 and PKD2 genes were mapped and cloned. […] The gene products, polycystin-1 and polycystin-2, are trans-membranous glycoproteins and are considered to be involved in signalling pathways, in cooperation with additional partners. […] Recent experimentation from various laboratories has shown that loss of heterozygosity and acquired somatic second hits may account, at least partly, for the inter- and intrafamilial phenotypic heterogeneity of the disease, while at the same time, the existence of other modifying loci is also hypothesized. […] The two-hit hypothesis is admittedly a very attractive one in that it can explain many of the features of the disease, whereas recent data regarding a trans-heterozygous model for cystogenesis adds to the complexity of the molecular mechanisms that can lead to pathogenesis.

• #11 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.

• #12 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 typical manifestation of ADPKD is the formation of renal cysts. Cysts are formed in about 1% to 3% of nephrons. Kidney cysts are formed already prenatally but they are mostly detected in adults. The cyst development and enlargement include numerous cellular changes. The resulting changes in polycystin expression cause the damage of several intracellular signaling pathways terminating in the development of cysts due to cell proliferation and fluid secretion.

• #13 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/

  The rapid development of cysts in the mature kidney might require a third hit in addition to the inactivation of both Pkd1 alleles. […] 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. […] The mechanism of cyst formation in ADPKD has been comprehensively analyzed in recent years, improving the originally proposed two-hit model. […] Abnormalities in planar cell polarity (PCP) have also been proposed to participate in cyst formation and growth, by perturbing the process of organized epithelial cell division along the longitudinal axis, necessary for tubule formation and elongation. […] The ADPKD cyst-lining epithelial cells are characterized by high rates of proliferation and apoptosis, dedifferentiation, planar polarity defects, and a secretory behavior.

• #14 Mechanism accelerates polycystic kidney disease | ScienceDaily

  https://www.sciencedaily.com/releases/2019/08/190826121932.htm

  Researchers uncover a previously unrecognized mechanism that may accelerate polycystic kidney disease. […] In a step toward disrupting the cycle that leads to cyst formation in the kidneys, the Weimbs Lab has now uncovered a previously unrecognized mechanism that accelerates cystogenesis. […] The rapid dilation of the tubules that conduct waste away from the kidneys in the form of urine has been found to be a „third-hit” trigger that results in rapid cyst growth in those with ADPKD. […] In kidneys genetically preconditioned to form these cysts, we found that these crystals can trigger the same dilation, but instead of going back to normal those tubules overshoot and form cysts. […] In individuals with ADPKD, the rapid and constant tubule dilation is seen as a „third hit” physical injury that results in cyst formation.

• #15 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20190826/Polycystic-kidney-disease-may-be-preventable.aspx

  ADPKD is due to a genetic mutation in one of two genes called the PKD1 or PKD2 genes, which produce the proteins polycystin1 (PC1) and polycystin-2 (PC2) respectively. However, the exact role they play in the disease is unknown. […] The search for the factor that eventually drives the progression of the disease led to the theory that ADPKD is a third-hit disease. In this model, three insults are required to trigger the formation of a cyst in the person with ADPKD. The first two hits are mutations which damage both members of either the paired PKD1 or PKD2 genes, of which one is inherited from the parents and the other random. While the first is present at birth, the second may occur later in life, after the kidney is mature. […] The third hit is another injury to the kidney, such as that caused by inadequate blood supply or a toxin, as a result of which a damage/repair sequence is switched on.

• #16 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  As an example, a dose of functional polycystin that falls below a critical threshold (approximately 10 to 30 percent of normal) within a tubular epithelial cell may be sufficient to initiate cyst formation. […] It has been proposed that falling below this threshold leads to abnormal fluid secretion, dysregulated cell proliferation, and apoptosis, which promote cyst growth via multiple signaling pathways. […] Increased fluid secretion into cysts, possibly mediated by the CFTR, appears to play a role in cyst growth. […] Fluid accumulation within ADPKD cysts is thought to be driven primarily by 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent chloride secretion. […] One hypothesis is that chloride transport across the apical membrane occurs via the CFTR. […] CFTR has been postulated to contribute to cyst growth.

• #17

  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.

• #18 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. […] The cyst-forming effect of kidney-specific inactivation of Kif3a, a gene that encodes an intraflagellar transport motor protein, was also dependent on the time when inactivation was induced.

• #19 Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3108786/

  Both autosomal dominant and recessive polycystic kidney disease are conditions with severe associated morbidity and mortality. Recent advances in the understanding of the genetic and molecular pathogenesis of both ADPKD and ARPKD have resulted in new, targeted therapies designed to disrupt cell signaling pathways responsible for the abnormal cell proliferation, dedifferentiation, apoptosis, and fluid secretion characteristic of the disease. […] 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.

• #20 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.

• #21 Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3108786/

  In response to fluid flow over the renal epithelium, the primary cilium is bent, resulting in a flow-induced increase in intracellular calcium. […] 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. […] 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. […] 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.

• #22 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.

• #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. […] Recent evidence suggests that disrupted PCP may play a role solely in the pathogenesis of ARPKD, as mouse models of PKD1 and PKD2 mutations have been found to lose cell-oriented division only after cyst formation has begun, unlike models of PKHD1.

• #24 Polycystic kidney disease – Wikipedia

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

  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 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. […] Recent evidence suggests that disrupted PCP may play a role solely in the pathogenesis of ARPKD, as mouse models of PKD1 and PKD2 mutations have been found to lose cell-oriented division only after cyst formation has begun, unlike models of PKHD1.

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

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

  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. […] 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.

• #27 Polycystic kidney disease – Wikipedia

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

  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.

• #28 Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3108786/

  In response to fluid flow over the renal epithelium, the primary cilium is bent, resulting in a flow-induced increase in intracellular calcium. […] 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. […] 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. […] 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.

• #29 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

  Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. […] The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. […] Although the exact mechanism behind cystogenesis is incompletely understood, a significant number of studies have attributed it to the alterations of different molecular signaling pathways that are regulated by genetic products of PKD1 and PKD2 that is polycystin-1 and polycystin-2, respectively found in primary cilia.

• #30 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. […] 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. […] 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.

• #31 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. […] 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. […] 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.

• #32 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.

• #33 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.

• #34 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/

  Several findings support essential roles for the polycystins in the control of cell proliferation and in the maintenance of a differentiated phenotype of renal tubular epithelium. […] The molecular basis for these phenotypic changes is largely unclear, but the recent identification of altered signaling pathways in the disease has provided some initial clues. […] The PC1-PC2 complex is thought to function as a mechano- or chemosensor in the cilia, translating extracellular stimuli into Ca2+ influx through PC2. […] The Ca2+ release from intracellular stores is reduced in the settings of PC2 absence, haploinsufficiency or overexpression. […] In this context, there is a defective homeostasis of intracellular Ca2+ in ADPKD, which apparently leads to intracellular accumulation of cAMP. […] In contrast to normal kidney epithelial cells, in which cAMP inhibits proliferation, ADPKD cells present an aberrant proliferative response to cAMP.

• #35

  https://link.springer.com/article/10.1007/s00018-007-7362-x

  Abnormalities in the basement-membrane composition and expression of matrix metalloproteases and their inhibitors were identified in PKD kidneys. […] It was recently discovered that defects in ciliary structure or function underlie multiple human diseases with diverse phenotypes, including retinal degeneration, neural tube defects, obesity, polydactyly and PKD. […] The primary cilia in the cystic kidney of mice with a mutation in the Tg737 gene (homologous to the IFT gene of Chlamydomonas, IFT88) are shorter than normal. […] Cells with mutated polycystin-1 fail to respond to the fluid flow: it was shown that in ADPKD-derived cells, the ciliary mechanosensation of fluid-flow shear stress by polycystins is absent. […] Thus, evidence of a direct link between cystoproteins, ciliary dysfunction and cell cycle dysregulation continues to accumulate.

• #36 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  Derangements in cAMP related to decreased intracellular calcium signaling may underlie the development of cysts via increased fluid secretion and cell proliferation. […] Activation of the mTOR protein may contribute to cyst growth in ADPKD. […] In contrast, inhibition of mTOR with rapamycin (sirolimus) preserved kidney function and inhibited epithelial cell proliferation and fibrosis in a mouse model of ADPKD in which the PKD1 gene was conditionally deleted. […] Angiogenesis may play a role in cyst growth and disease progression in ADPKD. […] Abnormalities of kidney cilia function may contribute to kidney cyst formation. […] The potential causes and consequences of cilia dysfunction in ADPKD remain unclear.

• #37 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  Derangements in cAMP related to decreased intracellular calcium signaling may underlie the development of cysts via increased fluid secretion and cell proliferation. […] Activation of the mTOR protein may contribute to cyst growth in ADPKD. […] In contrast, inhibition of mTOR with rapamycin (sirolimus) preserved kidney function and inhibited epithelial cell proliferation and fibrosis in a mouse model of ADPKD in which the PKD1 gene was conditionally deleted. […] Angiogenesis may play a role in cyst growth and disease progression in ADPKD. […] Abnormalities of kidney cilia function may contribute to kidney cyst formation. […] The potential causes and consequences of cilia dysfunction in ADPKD remain unclear.

• #38 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. […] 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. […] 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.

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

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

  Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). […] The Id pathway is associated with cell division. Id2 (Inhibitor of DNA binding 2) is a member of the helix-loop-helix family of proteins which bind to positively acting transcription factors and prevent them from binding to DNA. […] 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. […] 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. […] The canonical Wnt pathway is activated in cystic tissue of ADPKD patients. PC1 could affect the cystogenesis during embryogenesis by the influence on Wnt pathway.

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

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

  Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). […] The Id pathway is associated with cell division. Id2 (Inhibitor of DNA binding 2) is a member of the helix-loop-helix family of proteins which bind to positively acting transcription factors and prevent them from binding to DNA. […] 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. […] 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. […] The canonical Wnt pathway is activated in cystic tissue of ADPKD patients. PC1 could affect the cystogenesis during embryogenesis by the influence on Wnt pathway.

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

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

  Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). […] The Id pathway is associated with cell division. Id2 (Inhibitor of DNA binding 2) is a member of the helix-loop-helix family of proteins which bind to positively acting transcription factors and prevent them from binding to DNA. […] 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. […] 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. […] The canonical Wnt pathway is activated in cystic tissue of ADPKD patients. PC1 could affect the cystogenesis during embryogenesis by the influence on Wnt pathway.

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

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

  Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). […] The Id pathway is associated with cell division. Id2 (Inhibitor of DNA binding 2) is a member of the helix-loop-helix family of proteins which bind to positively acting transcription factors and prevent them from binding to DNA. […] 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. […] 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. […] The canonical Wnt pathway is activated in cystic tissue of ADPKD patients. PC1 could affect the cystogenesis during embryogenesis by the influence on Wnt pathway.

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

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

  Polycystins play a role in the cell cycle. Both polycystins modulate JAK-STAT pathway (The Janus kinase-signal transducers and activators of transcription). […] The Id pathway is associated with cell division. Id2 (Inhibitor of DNA binding 2) is a member of the helix-loop-helix family of proteins which bind to positively acting transcription factors and prevent them from binding to DNA. […] 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. […] 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. […] The canonical Wnt pathway is activated in cystic tissue of ADPKD patients. PC1 could affect the cystogenesis during embryogenesis by the influence on Wnt pathway.

• #44 Polycystic Kidney Disease: Pathogenesis and Potential Therapies

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

  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. […] The increased secretion might be expected to increase the hydrostatic pressure inside the cyst and encourage expansion, while the increase in cell proliferation would simultaneously induce de novo cyst formation. […] Both of the polycystin proteins exhibit complex subcellular localizations. […] 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. […] This model may explain, at least in part, why disease initiation occurs so long after the initial genetic insult.

• #45 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.

• #46 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).

• #47 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.

• #48 Autosomal Dominant Polycystic Kidney Disease – Genetics and Cyst Formation

  https://www.gavinpublishers.com/article/view/autosomal-dominant-polycystic-kidney-disease-genetics-and-cyst-formation

  Once the cysts grow to a size of 2-3cm, the cysts lose their connection to the functional nephron, and then being filling from secretion of fluid into the cysts. […] This cyst fluid has been shown (in culture) to harness a lipid secretory ability to promote cyst formation and fluid secretion. […] The observation that cysts develop in less than 10 percent of tubules and cystic dilation is focal has led to a second-hit theory of cyst formation for ADPKD Type I and Type II. This theory suggests that there is a developmental switch (first hit) and then there is the genetic mutation of PKD1 and PKD2 (second hit). […] There is yet another mechanism of cyst formation that may contribute to ADPKD cyst development. Na-K-ATPase pumps have been identified in ADPKD that are translocated from basolateral membrane to the luminal membrane.

• #49 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  As an example, a dose of functional polycystin that falls below a critical threshold (approximately 10 to 30 percent of normal) within a tubular epithelial cell may be sufficient to initiate cyst formation. […] It has been proposed that falling below this threshold leads to abnormal fluid secretion, dysregulated cell proliferation, and apoptosis, which promote cyst growth via multiple signaling pathways. […] Increased fluid secretion into cysts, possibly mediated by the CFTR, appears to play a role in cyst growth. […] Fluid accumulation within ADPKD cysts is thought to be driven primarily by 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent chloride secretion. […] One hypothesis is that chloride transport across the apical membrane occurs via the CFTR. […] CFTR has been postulated to contribute to cyst growth.

• #50 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  As an example, a dose of functional polycystin that falls below a critical threshold (approximately 10 to 30 percent of normal) within a tubular epithelial cell may be sufficient to initiate cyst formation. […] It has been proposed that falling below this threshold leads to abnormal fluid secretion, dysregulated cell proliferation, and apoptosis, which promote cyst growth via multiple signaling pathways. […] Increased fluid secretion into cysts, possibly mediated by the CFTR, appears to play a role in cyst growth. […] Fluid accumulation within ADPKD cysts is thought to be driven primarily by 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent chloride secretion. […] One hypothesis is that chloride transport across the apical membrane occurs via the CFTR. […] CFTR has been postulated to contribute to cyst growth.

• #51

  https://link.springer.com/article/10.1007/s00018-007-7362-x

  Chloride secretion drives sodium into the cystic cavity through paracellular mechanisms; this causes movement of water through aguaporins. […] The overlapping expression and localization patterns of polycystin-1 and -2 support their role as a complex in regulating multiple processes in tubular epithelia. […] Experimental evidence from several groups has established an important role for polycystins in epithelial cell morphogenesis, including differentiation and maturation in vivo. […] Because alterations in polycystin-1-mediated adhesion may cause the abnormal epithelial cell phenotype observed in ADPKD cells, including dedifferentiation and loss of epithelial polarity, several studies examined cell-cell adhesion junctions in primary cells derived from ADPKD kidneys. […] Polycystin-1 was shown to be indispensable in cell-matrix interactions.

• #52 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. […] 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.

• #53 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/

  The rapid development of cysts in the mature kidney might require a third hit in addition to the inactivation of both Pkd1 alleles. […] 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. […] The mechanism of cyst formation in ADPKD has been comprehensively analyzed in recent years, improving the originally proposed two-hit model. […] Abnormalities in planar cell polarity (PCP) have also been proposed to participate in cyst formation and growth, by perturbing the process of organized epithelial cell division along the longitudinal axis, necessary for tubule formation and elongation. […] The ADPKD cyst-lining epithelial cells are characterized by high rates of proliferation and apoptosis, dedifferentiation, planar polarity defects, and a secretory behavior.

• #54 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. […] 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.

• #55 Cystic Diseases of the Kidney: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/453831-overview

  The exact mechanism of genetically induced cyst formation has yet to be fully defined. Similarities between cystic diseases, however, reveal common pathologic pathways. The vast majority of mutations affect the primary cilia of the tubular epithelium, indicating that disruption of this structure relates to disease development. […] In both ADPKD and ARPKD, epidermal growth factor (EGF) has been identified as an important stimulus for proliferation of cystic epithelium. […] Biochemical analyses have identified a protein (mammalian target of rapamycin [mTOR]) that may be part of a common pathway in several of the genetic forms of cystic disease. Activity of mTOR is related to cell growth, proliferation, apoptosis, and differentiation. Increased levels of mTOR have been found in cyst epithelium. Under normal conditions, PC1 (mutated in ADPKD) and TSC2 (mutated in TS) suppress or inactivate mTOR. Mutations in these genes, as well as in others that relate to the primary cilia, result in dysregulation of mTOR activity, possibly allowing cyst formation.

• #56

  https://insight.jci.org/articles/view/135700

  Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. […] The treatment options for ADPKD are limited. […] We observed an upregulation in several IGF-1 pathway genes in the kidney of Pkd1RC/RC mice, a model of ADPKD. […] PAPP-A levels were high in cystic fluid and kidneys of humans with ADPKD. […] Our studies further showed that PAPP-A transcription in ADPKD was mainly regulated through the cAMP/CREB/CBP/p300 pathway. […] The role of PAPP-A in cystic disease appears to be regulation of the IGF-1 pathway and cellular proliferation in the kidney. […] These data indicated that the PAPP-A/IGF-1 pathway plays an important role in the growth and expansion of cysts in ADPKD. […] Our findings introduce a therapeutic strategy for ADPKD that involves the inhibition of PAPP-A.

• #57 Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3108786/

  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.

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

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

  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. […] 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.

• #59 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.

• #60

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

  A different role for PC1 and PC2 has also been suggested in the vasculature, whereby the ratio of the two proteins regulates pressure sensing, acting through stretch-activated ion channels. […] Macrophages appear early in developing organs to eliminate apoptotic cells and secrete trophic factors. […] A model for the contribution of macrophages to PKD progression. […] As described in cancer, a dialog between cystic cells and their inflammatory microenvironment may play an important role in the initiation and progression of PKD. […] Many advances have been made in understanding the pathogenesis of ADPKD since the identification of the disease genes nearly 20 years ago.

• #61

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

  A different role for PC1 and PC2 has also been suggested in the vasculature, whereby the ratio of the two proteins regulates pressure sensing, acting through stretch-activated ion channels. […] Macrophages appear early in developing organs to eliminate apoptotic cells and secrete trophic factors. […] A model for the contribution of macrophages to PKD progression. […] As described in cancer, a dialog between cystic cells and their inflammatory microenvironment may play an important role in the initiation and progression of PKD. […] Many advances have been made in understanding the pathogenesis of ADPKD since the identification of the disease genes nearly 20 years ago.

• #62 Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3108786/

  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.

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

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

  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. […] This reactivity is thought to be the result of altered intracellular calcium homeostasis and compensatory changes in transport proteins involved in calcium signaling, producing alteration of endothelium-dependent relaxation and increased systolic blood pressures.

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

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

  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. […] This reactivity is thought to be the result of altered intracellular calcium homeostasis and compensatory changes in transport proteins involved in calcium signaling, producing alteration of endothelium-dependent relaxation and increased systolic blood pressures.

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

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

  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. […] This reactivity is thought to be the result of altered intracellular calcium homeostasis and compensatory changes in transport proteins involved in calcium signaling, producing alteration of endothelium-dependent relaxation and increased systolic blood pressures.

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

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

  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. […] This reactivity is thought to be the result of altered intracellular calcium homeostasis and compensatory changes in transport proteins involved in calcium signaling, producing alteration of endothelium-dependent relaxation and increased systolic blood pressures.

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

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

  A decrease in urine-concentrating ability is an early manifestation of ADPKD. Plasma vasopressin levels are increased; this may represent the body’s attempt to compensate for the reduced concentrating capacity of the kidneys and could contribute to the development of renal cysts, hypertension, and kidney insufficiency.

• #68 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

  Polycystin 1 may regulate tubular epithelial cell adhesion and differentiation; polycystin 2 may function as an ion channel, with mutations causing fluid secretion into cysts. […] Mutations in these proteins may alter the function of renal cilia, which enable tubular cells to sense flow rates. 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.

• #69 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

  The epithelial cell proliferation causing increased cyst size and fluid accumulation are both processes mediated by an increase in cAMP when stimulated by anti-diuretic hormone (ADH). […] Eventually, cysts become so large that they become an autonomous unit. Drugs acting on V2 ADH receptors and consequently decreasing cAMP levels are the target treatment mechanism for ADPKD. […] Tolvaptan, a selective V2 receptor antagonist, was developed to reduce cAMP levels and slow down the initiation and progression of ADPKD. […] Once at the level of the kidney, 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.

• #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

  Vascular sclerosis and interstitial fibrosis eventually develop via unknown mechanisms and typically affect 10% of tubules; nonetheless, renal failure develops in about 35 to 45% of patients by age 60. […] Cyst and kidney volume measurements predict risk of progression to chronic kidney disease and end-stage kidney disease, often before changes in routine laboratory studies. […] Kidney size is the most important predictor for progression, particularly total kidney volume and end-stage kidney disease, often before changes in routine laboratory studies. […] Phosphaturic hormone fibroblast growth factor (FGF) 23 elevation was associated with increased kidney size and annualized rate of estimated glomerular filtration rate (eGFR) decline but interestingly did not enhance risk prediction for disease progression.

• #71 Molecular Mechanisms Underlying Polycystic Kidney Disease: From the Smallest Bricks to the Big Scenario | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/24275/molecular-mechanisms-underlying-polycystic-kidney-disease-from-the-smallest-bricks-to-the-big-scenario/magazine

  Polycystic Kidney Disease (PKD) is a genetically inherited disorder, caused by mutations in one of two genes, PKD1 or PKD2, encoding polycystin-1 (PC-1) or polycystin-2 (PC-2), respectively, leading to Autosomal Dominant Polycystic Kidney Disease (ADPKD), or mutations in the PKHD1 gene, encoding fibrocystin, causing Autosomal Recessive Polycystic Kidney Disease (ARPKD). […] Cyst development leads to organ enlargement and impaired function, and potentially lethal organ failure. […] PC-1, PC-2 and fibrocystin are transmembrane proteins, localized predominantly in the primary cilium, whose compromised expression impairs intracellular cAMP and calcium homeostasis, affecting many signaling pathways which involve mTOR, WNT, MYC, Hippo signaling, and many others. […] The goal of the present Research Topic is to provide a comprehensive overview of the most recent advances in the PKD field, ranging from ciliary signaling dysregulations to the metabolic dysfunction, from cyst formation and enlargement to fluid secretion and accumulation. […] A special focus is given to update recent progress in defining molecules of the primary cilium involved in cyst initiation.

• #72 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. […] 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); abnormal structure and/or function of the primary cilia; alterations in planar cell polarity; alterations in cell-cell and cell-matrix interactions. […] Mechanistic features of the cellular phenotype lead to the characteristic pathological features of cystic epithelia: a switch from well-differentiated, nonproliferative, resorptive epithelia to partially dedifferentiated, secretory epithelia characterized by specific polarization defects and high rates of proliferation and apoptosis.

• #73 Polycystic Kidney Disease: Pathogenesis and Potential Therapies

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

  Recent advances in the understanding of pathways governing renal cystogenesis have led to a number of intriguing possibilities for therapeutic intervention. […] Although disruptions in cilia formation or mutations in proteins that co-localize with the cilium are associated with renal cyst development, the exact relationship between cystogenesis and ciliogenesis is unclear.

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