Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist.
The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3',5'-cyclic monophosphate (cAMP) has a major role in cystogenesis, and the VPV2R is the major cAMP agonist in the collecting duct. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism*; D050396:TRPP Cation Channels
D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D001552:Benzazepines; D000242:Cyclic AMP; D011506:Proteins; D017483:Receptors, Vasopressin; D050396:TRPP Cation Channels; C496023:AQP2 protein, human; C496024:Aqp2 protein, mouse; C496025:Aqp2 protein, rat; C076251:mozavaptan