title: Adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity.
abstract: Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
authors.forename: Karl P
authors.initials: KP
authors.lastname: Roos
authors.forename: Vladislav
authors.initials: V
authors.lastname: Bugaj
authors.forename: Elena
authors.initials: E
authors.lastname: Mironova
authors.forename: James D
authors.initials: JD
authors.lastname: Stockand
authors.forename: Nirupama
authors.initials: N
authors.lastname: Ramkumar
authors.forename: Sara
authors.initials: S
authors.lastname: Rees
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000450:Aldosterone / Q000652:urine; D000818:Animals; D050034:Antidiuretic Agents / Q000378:metabolism / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D051399:Aquaporin 2 / Q000235:genetics; D001127:Arginine Vasopressin / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D050034:Antidiuretic Agents; D000959:Antihypertensive Agents; C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D053503:Epithelial Sodium Channels; C507047:Scnn1a protein, mouse; C507049:Scnn1b protein, mouse; C507053:Scnn1g protein, mouse; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D001127:Arginine Vasopressin; D000450:Aldosterone; D000068756:Valsartan; D012964:Sodium; D012083:Renin; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D014633:Valine