Key Points
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Polycystin-1 and polycystin-2 in the primary cilia and endoplasmic reticulum regulate intracellular calcium signalling; mutations in these proteins cause autosomal dominant polycystic kidney disease (ADPKD)
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In ADPKD, reduced intracellular calcium increases the generation of and inhibits the destruction of cAMP, and reduces the release of ATP
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Altered cAMP metabolism and purinergic signalling in collecting duct principal cells and distal nephron epithelial cells markedly increases the sensitivity of these cells to the constant tonic effects of vasopressin
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Increased protein kinase A activity leads to phosphorylation of polycystin-2, ryanodine receptors and inositol 1,4,5-trisphosphate receptors, increasing leakage of calcium from the endoplasmic reticulum, which further disrupts intracellular calcium signalling
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The reduction in intracellular calcium that results from mutant polycystin-1 or polycystin-2 causes the cellular response to cAMP to switch from suppression to stimulation of proliferation
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In vivo studies support the hypothesis that disruption of intracellular calcium signalling has a central role in the pathogenesis of ADPKD
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is responsible for 5–10% of cases of end-stage renal disease worldwide. ADPKD is characterized by the relentless development and growth of cysts, which cause progressive kidney enlargement associated with hypertension, pain, reduced quality of life and eventual kidney failure. Mutations in the PKD1 or PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, cause ADPKD. However, neither the functions of these proteins nor the molecular mechanisms of ADPKD pathogenesis are well understood. Here, we review the literature that examines how reduced levels of functional PC1 or PC2 at the primary cilia and/or the endoplasmic reticulum directly disrupts intracellular calcium signalling and indirectly disrupts calcium-regulated cAMP and purinergic signalling. We propose a hypothetical model in which dysregulated metabolism of cAMP and purinergic signalling increases the sensitivity of principal cells in collecting ducts and of tubular epithelial cells in the distal nephron to the constant tonic action of vasopressin. The resulting magnified response to vasopressin further enhances the disruption of calcium signalling that is initiated by mutations in PC1 or PC2, and activates downstream signalling pathways that cause impaired tubulogenesis, increased cell proliferation, increased fluid secretion and interstitial inflammation.
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Acknowledgements
The authors' work is supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK044863 and DK090728).
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V.E.T. is principal investigator for several clinical trials of tolvaptan in ADPKD and has received research support from Otsuka Pharmaceutical. The other authors declare no competing interests.
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Chebib, F., Sussman, C., Wang, X. et al. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol 11, 451–464 (2015). https://doi.org/10.1038/nrneph.2015.39
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DOI: https://doi.org/10.1038/nrneph.2015.39
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