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Angiotensin II Stimulates Vacuolar H⁺-ATPase Activity in Renal Acid-Secretory Intercalated Cells from the Outer Medullary Collecting Duct

Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

Correspondence: Dr. Carsten A. Wagner, Institute of Physiology and Centre for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Phone: +41-1-63-50659; Fax: +41-1-63-56814; E-mail: wagnerca{at}access.unizh.ch

Received for publication July 18, 2006. Accepted for publication April 10, 2007.

Final urinary acidification is mediated by the action of vacuolar H⁺-ATPases expressed in acid-secretory type A intercalated cells (A-IC) in the collecting duct. Angiotensin II (AngII) has profound effects on renal acid-base transport in the proximal tubule, distal tubule, and collecting duct. This study investigated the effects on vacuolar H⁺-ATPase activity in A-IC in freshly isolated mouse outer medullary collecting ducts. AngII (10 nM) stimulated concanamycin-sensitive vacuolar H⁺-ATPase activity in A-IC in freshly isolated mouse outer medullary collecting ducts via AT₁ receptors, which were also detected immunohistochemically in A-IC. AngII increased intracellular Ca²⁺ levels transiently. Chelation of intracellular Ca²⁺ with BAPTA and depletion of endoplasmic reticulum Ca²⁺ stores prevented the stimulatory effect on H⁺-ATPase activity. The effect of AngII on H⁺-ATPase activity was abolished by inhibitors of small G proteins and phospholipase C, by blockers of Ca²⁺-dependent and -independent isoforms of protein kinase C and extracellular signal–regulated kinase 1/2. Disruption of the microtubular network and cleavage of cellubrevin attenuated the stimulation. Finally, AngII failed to stimulate residual vacuolar H⁺-ATPase activity in A-IC from mice that were deficient for the B1 subunit of the vacuolar H⁺-ATPase. Thus, AngII presents a potent stimulus for vacuolar H⁺-ATPase activity in outer medullary collecting duct IC and requires trafficking of stimulatory proteins or vacuolar H⁺-ATPases. The B1 subunit is indispensable for the stimulation by AngII, and its importance for stimulation of vacuolar H⁺-ATPase activity may contribute to the inappropriate urinary acidification that is seen in patients who have distal renal tubular acidosis and mutations in this subunit.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673