Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat.
cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here it is shown that OPC-41061, an antagonist chosen for its potency and selectivity for human VPV2, is effective in PCK rats. PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061. These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys.
Wang
Xiaofang
X
Mayo Foundation, Rochester, Minnesota, USA.
Gattone
Vincent
V
Harris
Peter C
PC
Torres
Vicente E
VE
D000225:Adenine; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D017044:Polycystic Kidney, Autosomal Recessive / Q000517:prevention & control; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics; D013941:Thymine; D000077602:Tolvaptan; D018631:ras Proteins / Q000378:metabolism
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C479541:PKHD1 protein, rat; D011956:Receptors, Cell Surface; C076251:mozavaptan; D000077602:Tolvaptan; D006160:Guanosine Triphosphate; D000242:Cyclic AMP; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D000225:Adenine; D013941:Thymine