Materiały źródłowe

• #1 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. […] In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. […] The key or main molecular mechanism of cystogenesis in ARPKD remains unknown. Nevertheless, animal models have allowed us to expand our understanding of the different stages of the disease, from cyst formation to cyst progression. Throughout this complex process, several altered molecular pathways such as fluid secretion, abnormal cellular proliferation (such as mTOR, RAS-RAF-ERK and AKT), cAMP pathway regulated by PKA kinase and AC6, alterations in extracellular matrix (ECM), among others have been described.

• #2 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8235086/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. […] ARPKD is the recessive form of a group of heterogeneous monogenic disorders named polycystic kidney disease (PKD). The dominant form, autosomal dominant polycystic kidney disease (ADPKD), has a higher epidemiological prevalence and is typically diagnosed in adults.

• #3 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  The gene responsible for most ARPKD cases is Polycystic Kidney and Hepatic Disease 1 (PHKD1). The protein encoded by PKHD1 is fibrocystin (polyductin), a membrane protein found mainly in the distal tubules of the kidneys and biliary ducts of the liver. The exact function of this protein is somewhat uncertain, but it is thought to be involved in cellular adhesion, ciliary function, and cell proliferation. Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease).

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

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

  Autosomal recessive polycystic kidney disease (ARPKD) is a dual-organ hepatorenal disease with an incidence of 1:20,000 to 1:40,000 and a heterozygote carrier rate of 1 in 70. […] The genetic basis of both ADPKD and ARPKD have been identified, and delineation of the basic molecular and cellular pathophysiology has led to the discovery that abnormal ADPKD and ARPKD gene products interact to create polycystin complexes located at multiple sites within affected cells. […] ARPKD (OMIM 263200) belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant renal and liver-related morbidity and mortality in children. […] The ARPKD disease gene, PKHD1, encodes a 67-exon mRNA and is predicted to encode a protein of 4,074 amino acids called fibrocystin or polyductin.

• #5 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.

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

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

  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 Autosomal recessive polycystic kidney disease in children – UpToDate

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

  The DZIP1L gene is a second locus for ARPKD, although it is much less common than PKHD1. Variants in the DZIP1L gene were reported in seven patients with an atypical form of ARPKD from four unrelated consanguineous families. […] In animal models, the underlying pathogenesis appears to be due to compromised ciliary membrane translocation of the PKD proteins, polycystin-1 and -2.

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

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

  It has been challenging to correlate genotype with phenotype in PKHD1-associated ARPKD given the diversity of variants. […] The DZIP1L gene is a second locus for ARPKD, although it is much less common than PKHD1. Variants in the DZIP1L gene were reported in seven patients with an atypical form of ARPKD from four unrelated consanguineous families. […] In animal models, the underlying pathogenesis appears to be due to compromised ciliary membrane translocation of the PKD proteins, polycystin-1 and -2.

• #9 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor-γ (PPAR-γ) in animal models, or metabolic alterations. […] The cilia are long and microtubular structures emanating from the surface of mammalian cells. Pathologies related to a loss of proper cilia function are called ciliopathies, including ARPKD. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #10 Autosomal Recessive Polycystic Kidney Disease | Encyclopedia MDPI

  https://encyclopedia.pub/entry/11198

  In ARPKD, the first data were obtained from cpk mouse model renal extracts, which showed upregulation of EGF expression. […] Progressively, other evidence has shown a significant role for EGFR in vitro and murine models, and patients with ARPKD, where EGFR upregulation was located on the surface of the cystic epithelium. […] Several studies have shown that adenylyl cyclase adenosine 3′,5′-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. […] Production of cAMP is aberrant in the cyst epithelium, resulting in a large amount of this nucleotide in the cyst fluid. […] Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor-γ (PPAR-γ) in animal models, or metabolic alterations. […] The cilia are long and microtubular structures emanating from the surface of mammalian cells. Pathologies related to a loss of proper cilia function are called ciliopathies, including ARPKD.

• #11 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. Defects of the PKHD1 gene also cause embryologic ductal plate malformation, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #12 Autosomal Recessive Polycystic Kidney Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/19424

  Autosomal recessive polycystic kidney disease is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. The gene responsible for most ARPKD cases is Polycystic Kidney and Hepatic Disease 1 (PHKD1). The protein encoded by PKHD1 is fibrocystin (polyductin), a membrane protein found mainly in the distal tubules of the kidneys and biliary ducts of the liver. Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #13 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  The first evidence that the epidermal growth factor receptor (EGFR) axis was altered in PKD was in 1992, by demonstrating that cells from primary cultures of PKD patients increased cyst expansion. […] In ARPKD, the first data were obtained from cpk mouse model renal extracts, which showed upregulation of EGF expression. […] Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3′,5′-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. […] Dysregulation of calcium in PKD causes upregulation of the vasopressin V2 receptor, which activates the cAMP/PKA cascade.

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

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

  Evidence from multiple laboratories demonstrate a significant role for abnormalities in the EGFR axis in promoting epithelial hyperplasia and ensuing renal cyst formation and progressive enlargement in both murine and human ADPKD and ARPKD. […] Genetic complementation proved the mechanistic role of the abnormal EGFR axis phenotype in cystic disease. […] These data unequivocally establish a primary mechanistic role for the overexpression of the tyrosine kinase activity of the EGFR in the pathophysiology of renal cyst formation. […] The delineation of the molecular and cellular pathophysiology of PKD has led to a new era of pharmacological therapeutic intervention based on targeting of specific signaling abnormalities of cystic epithelia.

• #15 Autosomal recessive polycystic kidney disease: case report of a newborn with rare PKHD1 mutation, rapid renal enlargement and early fatal outcome | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-020-00922-4

  From a biochemical/molecular point of view, it has been supposed that proteins, like the epidermal growth factor receptor (EGFR), are abnormally expressed in the cystic renal epithelia of such patients. Their increased expression is associated with epithelial hyperplasia, leading to progressive enlargement of cysts. Moreover, in these subjects it has been observed an increased activation of the mTOR (mechanistic target of rapamycin kinase) signaling pathway. […] Despite recent advances in neonatal care, genetic knowledge, and excellent outcomes for pediatric kidney transplant, the 1-year mortality is still to date around 30%, and more often related to pulmonary hypoplasia, rather than to renal insufficiency. […] Unilateral or bilateral nephrectomy, with subsequent peritoneal dialysis, have been reported as therapeutic approach for selected subjects. The management of the severely affected neonates, therefore, focuses on MV and, occasionally, on unilateral or bilateral nephrectomy. Indeed, early removal of both fast-growing kidneys, pre-emptive peritoneal dialysis, since haemodialysis may be considered only when the peritoneal one is impossible to perform, and kidney transplantation, may be the most promising option in patients with respiratory impairment due to increased peri/postnatal growth of the kidneys.

• #16 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. […] In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. […] The key or main molecular mechanism of cystogenesis in ARPKD remains unknown. Nevertheless, animal models have allowed us to expand our understanding of the different stages of the disease, from cyst formation to cyst progression. Throughout this complex process, several altered molecular pathways such as fluid secretion, abnormal cellular proliferation (such as mTOR, RAS-RAF-ERK and AKT), cAMP pathway regulated by PKA kinase and AC6, alterations in extracellular matrix (ECM), among others have been described.

• #17 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. Defects of the PKHD1 gene also cause embryologic ductal plate malformation, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #18 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  The first evidence that the epidermal growth factor receptor (EGFR) axis was altered in PKD was in 1992, by demonstrating that cells from primary cultures of PKD patients increased cyst expansion. […] In ARPKD, the first data were obtained from cpk mouse model renal extracts, which showed upregulation of EGF expression. […] Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3′,5′-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. […] Dysregulation of calcium in PKD causes upregulation of the vasopressin V2 receptor, which activates the cAMP/PKA cascade.

• #19 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  The first evidence that the epidermal growth factor receptor (EGFR) axis was altered in PKD was in 1992, by demonstrating that cells from primary cultures of PKD patients increased cyst expansion. […] In ARPKD, the first data were obtained from cpk mouse model renal extracts, which showed upregulation of EGF expression. […] Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3′,5′-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. […] Dysregulation of calcium in PKD causes upregulation of the vasopressin V2 receptor, which activates the cAMP/PKA cascade.

• #20 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8235086/

  Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3,5-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. Production of cAMP is aberrant in the cyst epithelium, resulting in a large amount of this nucleotide in the cyst fluid. […] Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor- (PPAR-) in animal models, or metabolic alterations. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #21 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  The first evidence that the epidermal growth factor receptor (EGFR) axis was altered in PKD was in 1992, by demonstrating that cells from primary cultures of PKD patients increased cyst expansion. […] In ARPKD, the first data were obtained from cpk mouse model renal extracts, which showed upregulation of EGF expression. […] Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3′,5′-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. […] Dysregulation of calcium in PKD causes upregulation of the vasopressin V2 receptor, which activates the cAMP/PKA cascade.

• #22 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  The first evidence that the epidermal growth factor receptor (EGFR) axis was altered in PKD was in 1992, by demonstrating that cells from primary cultures of PKD patients increased cyst expansion. […] In ARPKD, the first data were obtained from cpk mouse model renal extracts, which showed upregulation of EGF expression. […] Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3′,5′-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. […] Dysregulation of calcium in PKD causes upregulation of the vasopressin V2 receptor, which activates the cAMP/PKA cascade.

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

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

  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. […] 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 Regenerative Therapy in Autosomal Recessive Polycystic Kidney Disease

  https://www.mathewsopenaccess.com/full-text/regenerative-therapy-in-autosomal-recessive-polycystic-kidney-disease

  Autosomal recessive polycystic kidney disease (ARPKD) is a developmental disease that results from fibrocystin loss of function mutation. […] The exact mechanism of how fibrocystin mutation results in the disease manifestations is not known as the exact functions of fibrocystin are not very well identified. One of the mechanisms involved in the development of ARPKD is the impaired epithelial cell polarity, which renders the epithelium secretory rather than absorptive. […] Pathogenesis of ARPKD involves three major processes; Proliferation of epithelial cells; Dilatation of the lumen; Secretion of fluid into the lumen. Accordingly, the epithelial cells of the renal collecting ducts, which line the growing cysts in ARPKD, secret fluid into cysts lumina. […] Loss of fibrocystin function leads to defective FAK activity. The expression of the 1 Na+ /K+ ATPase subunit is decreased for the sake of 2 subunit. Cellular polarization is disturbed and Na+ /K+ ATPase localizes to the apical rather than the lateral cellular borders which contributes to a major role in disease pathogenesis.

• #25 Regenerative Therapy in Autosomal Recessive Polycystic Kidney Disease

  https://www.mathewsopenaccess.com/full-text/regenerative-therapy-in-autosomal-recessive-polycystic-kidney-disease

  Autosomal recessive polycystic kidney disease (ARPKD) is a developmental disease that results from fibrocystin loss of function mutation. […] The exact mechanism of how fibrocystin mutation results in the disease manifestations is not known as the exact functions of fibrocystin are not very well identified. One of the mechanisms involved in the development of ARPKD is the impaired epithelial cell polarity, which renders the epithelium secretory rather than absorptive. […] Pathogenesis of ARPKD involves three major processes; Proliferation of epithelial cells; Dilatation of the lumen; Secretion of fluid into the lumen. Accordingly, the epithelial cells of the renal collecting ducts, which line the growing cysts in ARPKD, secret fluid into cysts lumina. […] Loss of fibrocystin function leads to defective FAK activity. The expression of the 1 Na+ /K+ ATPase subunit is decreased for the sake of 2 subunit. Cellular polarization is disturbed and Na+ /K+ ATPase localizes to the apical rather than the lateral cellular borders which contributes to a major role in disease pathogenesis.

• #26 Regenerative Therapy in Autosomal Recessive Polycystic Kidney Disease

  https://www.mathewsopenaccess.com/full-text/regenerative-therapy-in-autosomal-recessive-polycystic-kidney-disease

  Taken together, the decreased expression of 1 Na+ /K+ ATPase subunit, which is necessary for the E-cadherin mediated establishment of cell polarity, and decreased activation of FAK, which interacts with adhesion proteins and is essential for the establishment of the polarized cell migration, both together may explain how Fibrocystin loss of function mutation can result in the reversed epithelial cell polarity and the intra-cystic secretion in ARPKD. […] Accordingly, the experimental proof of the above scenario could be favored if: Defective expression of Fibrocystin was reflected on the FAK expression/function. In the ARPKD cells, where the expression of 1 Na+ /K+ ATPase subunit is defective, Src expression is enhanced. […] Accordingly, it could be concluded that the impaired epithelial cellular polarity seen in ARPKD might result from the impaired 1 /2 Na+/K+ ATPase expression together with the impaired FAK activation and function, with the possible involvement of the adhesion signalling in the development of those interactions. Restoration of the functions of FAK and 1 Na+ /K+ ATPase in the renal and biliary epithelia of ARPKD patients could be a future hope of recovery that could be achieved through the regenerative therapy, using stem cells that express myroslated FAK and 1 Na+/K+ ATPase subunit to slowdown or reverse cyst formation.

• #27 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. Defects of the PKHD1 gene also cause embryologic ductal plate malformation, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #28 Autosomal Recessive Polycystic Kidney Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/19424

  Autosomal recessive polycystic kidney disease is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. The gene responsible for most ARPKD cases is Polycystic Kidney and Hepatic Disease 1 (PHKD1). The protein encoded by PKHD1 is fibrocystin (polyductin), a membrane protein found mainly in the distal tubules of the kidneys and biliary ducts of the liver. Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #29 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor-γ (PPAR-γ) in animal models, or metabolic alterations. […] The cilia are long and microtubular structures emanating from the surface of mammalian cells. Pathologies related to a loss of proper cilia function are called ciliopathies, including ARPKD. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #30 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor-γ (PPAR-γ) in animal models, or metabolic alterations. […] The cilia are long and microtubular structures emanating from the surface of mammalian cells. Pathologies related to a loss of proper cilia function are called ciliopathies, including ARPKD. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #31 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor-γ (PPAR-γ) in animal models, or metabolic alterations. […] The cilia are long and microtubular structures emanating from the surface of mammalian cells. Pathologies related to a loss of proper cilia function are called ciliopathies, including ARPKD. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #32 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. Defects of the PKHD1 gene also cause embryologic ductal plate malformation, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #33 Autosomal Recessive Polycystic Kidney Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/19424

  Autosomal recessive polycystic kidney disease is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. The gene responsible for most ARPKD cases is Polycystic Kidney and Hepatic Disease 1 (PHKD1). The protein encoded by PKHD1 is fibrocystin (polyductin), a membrane protein found mainly in the distal tubules of the kidneys and biliary ducts of the liver. Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #34 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1α) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor-γ (PPAR-γ) in animal models, or metabolic alterations. […] The cilia are long and microtubular structures emanating from the surface of mammalian cells. Pathologies related to a loss of proper cilia function are called ciliopathies, including ARPKD. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #35 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8235086/

  Epithelial secretion is a key physiopathology component of cyst formation. Reduced sodium uptake in ARPKD net fluid secretion has been proposed as being related to decreased EGF in the alpha subunit of the epithelial Na channel. […] Several studies have shown that adenylyl cyclase adenosine 3,5-cyclic monophosphate (cAMP) pathway stimulates cell proliferation in the renal epithelium of ARPKD and ADPKD. Production of cAMP is aberrant in the cyst epithelium, resulting in a large amount of this nucleotide in the cyst fluid. […] Other pathogenic features have been identified in ARPKD, as well as alterations in extracellular matrix (ECM) and metalloproteinase expression (MMPs), upregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1) in Pkhd1 deficient cells, upregulation of peroxisome-proliferator-activated receptor- (PPAR-) in animal models, or metabolic alterations. […] The results of these studies appear consistent with the idea that the PKD proteins form a functional complex in cilia with common downstream signaling pathways.

• #36 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. […] 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. […] Additional evidence for the role of the primary cilium in PKD comes from the finding that transgenic mice with kidney-specific knockouts of Kif3a, a motor protein subunit required for cilia formation, produce renal cysts in mice similar to those seen in human 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).

• #37 Autosomal recessive polycystic kidney disease – Wikipedia

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

  Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD. […] The cause of ARPKD is linked to mutations in the PKHD1 gene. The PKHD1 gene encodes for the protein for fibrocystin, that is found in the epithelial cells of both the renal tubule and the bile ducts; deficiency leads to the characteristic polycystic dilation of both structures. […] It is known that FPC interacts with ADPKD protein PC2 and may also participate in this regulation pathway of the mechanosensory function of the primary cilia, calcium signaling, and PCP. This is suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. […] There have been a large number of various single-gene mutations found throughout PKHD1 and are unique to individual families. Most of the patients are compound heterozygotes for PKHD1 mutations. Patients with two nonsense mutations appear to have an earlier onset of the disease.

• #38 Polycystic kidney disease pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Polycystic_kidney_disease_pathophysiology

  It is suggested that fibrocystin may be involved in regulation of cellular adhesion and proliferation. […] Malfunction in fibrocystin leads to cyst formation by forming an undifferentiated secretory epithelium. […] This defect leads to polarization abnormalities and high rate of proliferation and apoptosis. […] There is a subsequent increase in cAMP signaling, epidermal growth factor receptor axis mediated proliferation and excess fluid secretion.

• #39 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. […] In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. […] The key or main molecular mechanism of cystogenesis in ARPKD remains unknown. Nevertheless, animal models have allowed us to expand our understanding of the different stages of the disease, from cyst formation to cyst progression. Throughout this complex process, several altered molecular pathways such as fluid secretion, abnormal cellular proliferation (such as mTOR, RAS-RAF-ERK and AKT), cAMP pathway regulated by PKA kinase and AC6, alterations in extracellular matrix (ECM), among others have been described.

• #40 SciELO Brazil – Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/3zBFLVBxzc9DxTGTxTschgG/?lang=en

  Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disease characterized by a malformation complex which includes cystically dilated tubules in the kidneys and ductal plate malformation in the liver. […] All typical forms of ARPKD are caused by mutations in a single gene, PKHD1 (polycystic kidney and hepatic disease 1). […] This product, polyductin, is a 4,074-amino acid protein expressed in the cytoplasm, plasma membrane and primary apical cilia, a structure that has been implicated in the pathogenesis of different polycystic kidney diseases. […] In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology. […] Polyductin seems also to participate in tubule morphogenesis and cell mitotic orientation along the tubular axis.

• #41 SciELO Brazil – Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/3zBFLVBxzc9DxTGTxTschgG/?lang=en

  The recent advances in the understanding of in vitro and animal models of polycystic kidney diseases have shed light on the molecular and cellular mechanisms of cyst formation and progression, allowing the initiation of therapeutic strategy designing and promising perspectives for ARPKD patients. […] It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD. […] The primary cilium develops from a modified centriole, the basal body. Its assembly and maintenance depend on the transport of proteins between the cilia and the cytoplasm, a process called intraflagellar transport (IFT). […] Several studies have shown that proteins translated from genes mutated in different human polycystic kidney diseases (PKD) and PKD animal models are expressed in the primary cilium.

• #42 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20220922/New-modeling-system-identifies-potential-therapeutics-for-autosomal-recessive-polycystic-kidney-disease.aspx

  They also shed light on two important questions regarding the disease mechanisms of ARPKD: That the molecule FOS may be a crucial determent of species-specific cyst formation, which explains why mouse models were unable to effectively replicate the disease; Why mutations in the PKHD1 gene lead to cyst formation. […] In this study, we showed that our kidney organoids on a chip platform provides a physiologically relevant model for ARPKD, allowing the identification of mechanosensing signals as key drivers of cystogenesis.

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

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

  Evidence from multiple laboratories demonstrate a significant role for abnormalities in the EGFR axis in promoting epithelial hyperplasia and ensuing renal cyst formation and progressive enlargement in both murine and human ADPKD and ARPKD. […] Genetic complementation proved the mechanistic role of the abnormal EGFR axis phenotype in cystic disease. […] These data unequivocally establish a primary mechanistic role for the overexpression of the tyrosine kinase activity of the EGFR in the pathophysiology of renal cyst formation. […] The delineation of the molecular and cellular pathophysiology of PKD has led to a new era of pharmacological therapeutic intervention based on targeting of specific signaling abnormalities of cystic epithelia.

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

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

  Evidence from multiple laboratories demonstrate a significant role for abnormalities in the EGFR axis in promoting epithelial hyperplasia and ensuing renal cyst formation and progressive enlargement in both murine and human ADPKD and ARPKD. […] Genetic complementation proved the mechanistic role of the abnormal EGFR axis phenotype in cystic disease. […] These data unequivocally establish a primary mechanistic role for the overexpression of the tyrosine kinase activity of the EGFR in the pathophysiology of renal cyst formation. […] The delineation of the molecular and cellular pathophysiology of PKD has led to a new era of pharmacological therapeutic intervention based on targeting of specific signaling abnormalities of cystic epithelia.

• #45 SciELO Brazil – Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/3zBFLVBxzc9DxTGTxTschgG/?lang=en

  The recent advances in the understanding of in vitro and animal models of polycystic kidney diseases have shed light on the molecular and cellular mechanisms of cyst formation and progression, allowing the initiation of therapeutic strategy designing and promising perspectives for ARPKD patients. […] It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD. […] The primary cilium develops from a modified centriole, the basal body. Its assembly and maintenance depend on the transport of proteins between the cilia and the cytoplasm, a process called intraflagellar transport (IFT). […] Several studies have shown that proteins translated from genes mutated in different human polycystic kidney diseases (PKD) and PKD animal models are expressed in the primary cilium.

• #46 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.

• #47 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20220922/New-modeling-system-identifies-potential-therapeutics-for-autosomal-recessive-polycystic-kidney-disease.aspx

  They also shed light on two important questions regarding the disease mechanisms of ARPKD: That the molecule FOS may be a crucial determent of species-specific cyst formation, which explains why mouse models were unable to effectively replicate the disease; Why mutations in the PKHD1 gene lead to cyst formation. […] In this study, we showed that our kidney organoids on a chip platform provides a physiologically relevant model for ARPKD, allowing the identification of mechanosensing signals as key drivers of cystogenesis.

• #48 Regenerative Therapy in Autosomal Recessive Polycystic Kidney Disease

  https://www.mathewsopenaccess.com/full-text/regenerative-therapy-in-autosomal-recessive-polycystic-kidney-disease

  Taken together, the decreased expression of 1 Na+ /K+ ATPase subunit, which is necessary for the E-cadherin mediated establishment of cell polarity, and decreased activation of FAK, which interacts with adhesion proteins and is essential for the establishment of the polarized cell migration, both together may explain how Fibrocystin loss of function mutation can result in the reversed epithelial cell polarity and the intra-cystic secretion in ARPKD. […] Accordingly, the experimental proof of the above scenario could be favored if: Defective expression of Fibrocystin was reflected on the FAK expression/function. In the ARPKD cells, where the expression of 1 Na+ /K+ ATPase subunit is defective, Src expression is enhanced. […] Accordingly, it could be concluded that the impaired epithelial cellular polarity seen in ARPKD might result from the impaired 1 /2 Na+/K+ ATPase expression together with the impaired FAK activation and function, with the possible involvement of the adhesion signalling in the development of those interactions. Restoration of the functions of FAK and 1 Na+ /K+ ATPase in the renal and biliary epithelia of ARPKD patients could be a future hope of recovery that could be achieved through the regenerative therapy, using stem cells that express myroslated FAK and 1 Na+/K+ ATPase subunit to slowdown or reverse cyst formation.

• #49 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. Defects of the PKHD1 gene also cause embryologic ductal plate malformation, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #50 Autosomal Recessive Polycystic Kidney Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/19424

  Autosomal recessive polycystic kidney disease is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. ARPKD is characterized by renal distal tubule and collecting duct cyst formation, hepatic biliary duct ectasia/malformation, and fibrosis involving both the liver and kidneys. ARPKD is a ciliopathy and presents with cysts along the distal renal tubules and collecting ducts, compared to ADPKD, where the cysts can develop anywhere along the nephron. The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. The abnormal proliferation of renal tubule epithelium causes them to lose their normal physiological function, and they fill with fluid from transepithelial secretion. The fluid is rich in epithelial growth factors, which leads to further proliferation of epithelial cells. This leads to extracellular matrix deposition and increased cytokines, growth factors, and inflammation. All these factors lead to renal fibrosis, proximal tubule apoptosis, and loss of kidney function. Later in the disease, the kidney becomes massively enlarged with macrocysts and interstitial fibrosis similar to the presentation of ADPKD. The gene responsible for most ARPKD cases is Polycystic Kidney and Hepatic Disease 1 (PHKD1). The protein encoded by PKHD1 is fibrocystin (polyductin), a membrane protein found mainly in the distal tubules of the kidneys and biliary ducts of the liver. Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #51 Autosomal recessive polycystic kidney disease: case report of a newborn with rare PKHD1 mutation, rapid renal enlargement and early fatal outcome | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-020-00922-4

  This patient report may provide further insights into the molecular pathogenesis of ARPKD, as well as a better genomic and clinical characterization of the disease. The hope for the next future may come from the ever-deeper knowledge of the underlying genomic/molecular mechanisms, which may lead to effective therapies.

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