Polycystic kidney disease pathophysiology: Difference between revisions
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*The pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) stems from the mutations of PKD1 and PKD2 genes on chromosomes 16 and 4 respectively. | *The pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) stems from the mutations of PKD1 and PKD2 genes on chromosomes 16 and 4 respectively. | ||
*Polycystin-1 and polycystin-2, the protein products of PKD1 and PKD2, are transmembrane proteins that have distinct functions but interact to form one functional complex explaining the similar phenotype with both mutations.<ref name="pmid7663510">{{cite journal| author=Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL et al.| title=The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. | journal=Nat Genet | year= 1995 | volume= 10 | issue= 2 | pages= 151-60 | pmid=7663510 | doi=10.1038/ng0695-151 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7663510 }} </ref><ref name="pmid9286709">{{cite journal| author=Hayashi T, Mochizuki T, Reynolds DM, Wu G, Cai Y, Somlo S| title=Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). | journal=Genomics | year= 1997 | volume= 44 | issue= 1 | pages= 131-6 | pmid=9286709 | doi=10.1006/geno.1997.4851 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9286709 }} </ref><ref name="pmid9171830">{{cite journal| author=Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG| title=PKD1 interacts with PKD2 through a probable coiled-coil domain. | journal=Nat Genet | year= 1997 | volume= 16 | issue= 2 | pages= 179-83 | pmid=9171830 | doi=10.1038/ng0697-179 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9171830 }} </ref> | *Polycystin-1 and polycystin-2, the protein products of PKD1 and PKD2, are transmembrane proteins that have distinct functions but interact to form one functional complex explaining the similar phenotype with both mutations.<ref name="pmid7663510">{{cite journal| author=Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL et al.| title=The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. | journal=Nat Genet | year= 1995 | volume= 10 | issue= 2 | pages= 151-60 | pmid=7663510 | doi=10.1038/ng0695-151 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7663510 }} </ref><ref name="pmid9286709">{{cite journal| author=Hayashi T, Mochizuki T, Reynolds DM, Wu G, Cai Y, Somlo S| title=Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). | journal=Genomics | year= 1997 | volume= 44 | issue= 1 | pages= 131-6 | pmid=9286709 | doi=10.1006/geno.1997.4851 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9286709 }} </ref><ref name="pmid9171830">{{cite journal| author=Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG| title=PKD1 interacts with PKD2 through a probable coiled-coil domain. | journal=Nat Genet | year= 1997 | volume= 16 | issue= 2 | pages= 179-83 | pmid=9171830 | doi=10.1038/ng0697-179 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9171830 }} </ref> | ||
*Polycystin-1 is a ligand receptor | **Polycystin-1 is a ligand receptor | ||
*Polycystin-2 is a non-selective cation channel. | **Polycystin-2 is a non-selective cation channel. | ||
*Both proteins are located in the primary cilium in the renal tubular epithelial cells, which is typical of many other proteins also implicated in cystic diseases of the kidneys. | **Both proteins are located in the primary cilium in the renal tubular epithelial cells, which is typical of many other proteins also implicated in cystic diseases of the kidneys. | ||
*Despite their location, the primary cilia are usually structurally normal in ADPKD. However, functional abnormalities in mechanosensation have been documented.<ref name="pmid17429048">{{cite journal| author=Chapman AB| title=Autosomal dominant polycystic kidney disease: time for a change? | journal=J Am Soc Nephrol | year= 2007 | volume= 18 | issue= 5 | pages= 1399-407 | pmid=17429048 | doi=10.1681/ASN.2007020155 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17429048 }} </ref> In wildtype variants, the polycystin protein complex detects changes in tubular flow, with resultant changes in Ca²+ influx via the polycystin-2 channel. This mechanism is defective in patients with ADPKD.<ref name="pmid12514735">{{cite journal| author=Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X et al.| title=Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. | journal=Nat Genet | year= 2003 | volume= 33 | issue= 2 | pages= 129-37 | pmid=12514735 | doi=10.1038/ng1076 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12514735 }} </ref> | *Despite their location, the primary cilia are usually structurally normal in ADPKD. However, functional abnormalities in mechanosensation have been documented.<ref name="pmid17429048">{{cite journal| author=Chapman AB| title=Autosomal dominant polycystic kidney disease: time for a change? | journal=J Am Soc Nephrol | year= 2007 | volume= 18 | issue= 5 | pages= 1399-407 | pmid=17429048 | doi=10.1681/ASN.2007020155 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17429048 }} </ref> In wildtype variants, the polycystin protein complex detects changes in tubular flow, with resultant changes in Ca²+ influx via the polycystin-2 channel. This mechanism is defective in patients with ADPKD.<ref name="pmid12514735">{{cite journal| author=Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X et al.| title=Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. | journal=Nat Genet | year= 2003 | volume= 33 | issue= 2 | pages= 129-37 | pmid=12514735 | doi=10.1038/ng1076 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12514735 }} </ref> | ||
*Even before polycystins were discovered, cyst formation was considered to be the result of 3 processes: | *Even before polycystins were discovered, cyst formation was considered to be the result of 3 processes: | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul
Overview
The pathogenesis of ADPKD is related to the protein products of the PKD1 and PKD2 genes known collectively as polycystins. These proteins are mainly involved in ciliary function in the renal tubular cells, and defects in their function leads to intracellular cAMP accumulation and mTOR overactivity causing cell proliferation, fluid secretion, and abnormal extracellular matrix and intercellular interactions the main processes that lead to cyst formation.
Pathophysiology
Pathogenesis
- The pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) stems from the mutations of PKD1 and PKD2 genes on chromosomes 16 and 4 respectively.
- Polycystin-1 and polycystin-2, the protein products of PKD1 and PKD2, are transmembrane proteins that have distinct functions but interact to form one functional complex explaining the similar phenotype with both mutations.[1][2][3]
- Polycystin-1 is a ligand receptor
- Polycystin-2 is a non-selective cation channel.
- Both proteins are located in the primary cilium in the renal tubular epithelial cells, which is typical of many other proteins also implicated in cystic diseases of the kidneys.
- Despite their location, the primary cilia are usually structurally normal in ADPKD. However, functional abnormalities in mechanosensation have been documented.[4] In wildtype variants, the polycystin protein complex detects changes in tubular flow, with resultant changes in Ca²+ influx via the polycystin-2 channel. This mechanism is defective in patients with ADPKD.[5]
- Even before polycystins were discovered, cyst formation was considered to be the result of 3 processes:
- Cell proliferation
- Fluid secretion
- Abnormal extracellular matrix and intercellular interactions
- With the relatively recent advances in the pathogenesis of ADPKD, polycystins were found to regulate all these processes.[4]
- With the alterations in calcium hemostasis within tubular cells, intracellular cAMP concentration increase causing apical cAMP-dependent Cl channels to increase cyst fluid secretion activate cellular proliferation via extracellular signaling.[6]
- These findings have made intracellular cAMP concentrations the focal point for targeted therapy in ADPKD.[4]
- Another proposed mechanism of pathogenesis involved increased mTOR activity.
- Normally, polycystin1 is involved in suppressing the activity of mTOR , explaining the abnormally increased activity seen in ADPKD.
- mTOR is heavily in involved cell growth and proliferation with suggested involvement in increased cellular proliferation and apoptosis seen in ADPKD.[7]
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Associated Conditions
- Berry aneurysms
- Mitral valve prolapse
- Benign hepatic cysts
- Congenital hepatic fibrosis
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL; et al. (1995). "The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains". Nat Genet. 10 (2): 151–60. doi:10.1038/ng0695-151. PMID 7663510.
- ↑ Hayashi T, Mochizuki T, Reynolds DM, Wu G, Cai Y, Somlo S (1997). "Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2)". Genomics. 44 (1): 131–6. doi:10.1006/geno.1997.4851. PMID 9286709.
- ↑ Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG (1997). "PKD1 interacts with PKD2 through a probable coiled-coil domain". Nat Genet. 16 (2): 179–83. doi:10.1038/ng0697-179. PMID 9171830.
- ↑ 4.0 4.1 4.2 Chapman AB (2007). "Autosomal dominant polycystic kidney disease: time for a change?". J Am Soc Nephrol. 18 (5): 1399–407. doi:10.1681/ASN.2007020155. PMID 17429048.
- ↑ Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X; et al. (2003). "Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells". Nat Genet. 33 (2): 129–37. doi:10.1038/ng1076. PMID 12514735 Check
|pmid=value (help). - ↑ Belibi FA, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H; et al. (2004). "Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells". Kidney Int. 66 (3): 964–73. doi:10.1111/j.1523-1755.2004.00843.x. PMID 15327388.
- ↑ Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N; et al. (2006). "The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease". Proc Natl Acad Sci U S A. 103 (14): 5466–71. doi:10.1073/pnas.0509694103. PMC 1459378. PMID 16567633 Check
|pmid=value (help).