title: Vasopressin and disruption of calcium signalling in polycystic kidney disease.
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.
authors: Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA.
authors: Fouad T
authors: FT
authors: Chebib
authors: Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA.
authors: Caroline R
authors: CR
authors: Sussman
authors: Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA.
authors: Xiaofang
authors: X
authors: Wang
authors: Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA.
authors: Peter C
authors: PC
authors: Harris
authors: Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA.
authors: Vicente E
authors: VE
authors: Torres
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum; D006801:Humans; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology*; D011983:Receptors, Purinergic / Q000502:physiology; D012519:Sarcoplasmic Reticulum; D050396:TRPP Cation Channels / Q000502:physiology; D014667:Vasopressins / Q000502:physiology*
chemical_list: D011983:Receptors, Purinergic; D050396:TRPP Cation Channels; D014667:Vasopressins; D000242:Cyclic AMP