title: Aldosterone stimulates vacuolar H(+)-ATPase activity in renal acid-secretory intercalated cells mainly via a protein kinase C-dependent pathway.
abstract: Urinary acidification in the collecting duct is mediated by the activity of H(+)-ATPases and is stimulated by various factors including angiotensin II and aldosterone. Classically, aldosterone effects are mediated via the mineralocorticoid receptor. Recently, we demonstrated a nongenomic stimulatory effect of aldosterone on H(+)-ATPase activity in acid-secretory intercalated cells of isolated mouse outer medullary collecting ducts (OMCD). Here we investigated the intracellular signaling cascade mediating this stimulatory effect. Aldosterone stimulated H(+)-ATPase activity in isolated mouse and human OMCDs. This effect was blocked by suramin, a general G protein inhibitor, and GP-2A, a specific G(αq) inhibitor, whereas pertussis toxin was without effect. Inhibition of phospholipase C with U-73122, chelation of intracellular Ca(2+) with BAPTA, and blockade of protein kinase C prevented the stimulation of H(+)-ATPases. Stimulation of PKC by DOG mimicked the effect of aldosterone on H(+)-ATPase activity. Similarly, aldosterone and DOG induced a rapid translocation of H(+)-ATPases to the luminal side of OMCD cells in vivo. In addition, PD098059, an inhibitor of ERK1/2 activation, blocked the aldosterone and DOG effects. Inhibition of PKA with H89 or KT2750 prevented and incubation with 8-bromoadenosine-cAMP mildly increased H(+)-ATPase activity. Thus, the nongenomic modulation of H(+)-ATPase activity in OMCD-intercalated cells by aldosterone involves several intracellular pathways and may be mediated by a G(αq) protein-coupled receptor and PKC. PKA and cAMP appear to have a modulatory effect. The rapid nongenomic action of aldosterone may participate in the regulation of H(+)-ATPase activity and contribute to final urinary acidification.
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Winter
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Kampik
authors.forename: Luca
authors.initials: L
authors.lastname: Vedovelli
authors.forename: Florina
authors.initials: F
authors.lastname: Rothenberger
authors.forename: Teodor G
authors.initials: TG
authors.lastname: Paunescu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stehberger
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Hubert
authors.initials: H
authors.lastname: John
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D004075:Diglycerides; D004791:Enzyme Inhibitors; D004963:Estrenes; D005419:Flavonoids; D007546:Isoquinolines; D011760:Pyrrolidinones; D013449:Sulfonamides; C044295:1,2-dioctanoylglycerol; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000450:Aldosterone; D004533:Egtazic Acid; D013498:Suramin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D025262:Vacuolar Proton-Translocating ATPases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one