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Thiazolidinedione-Induced Fluid Retention Is Independent of Collecting Duct ENaC Activity

Volker Vallon^*, Edith Hummler, Timo Rieg^*, Oleh Pochynyuk, Vladislav Bugaj, Jana Schroth^*, Georges Dechenes, Bernard Rossier, Robyn Cunard^* and James Stockand

^* Nephrology and Hypertension, Department of Medicine, University of California, San Diego, and Veterans Affairs San Diego Healthcare System, San Diego, and Department of Pharmacology, University of California, San Diego, La Jolla, California; Department of Pharmacology, University of Lausanne, Lausanne, Switzerland; Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and Assistance Publique–Hôpitaux de Paris, Hôpital Robert-Debré, Paris, France

Correspondence: Dr. Volker Vallon, Departments of Medicine and Pharmacology, University of California San Diego & VASDHCS, 3350 La Jolla Village Drive (9151), San Diego, CA 92161. Phone: 858-552-8585 ext. 5945; Fax: 858-642-1438; E-mail: vvallon{at}ucsd.edu

Received for publication April 23, 2008. Accepted for publication October 14, 2008.

Thiazolidinediones are agonists of peroxisome proliferator–activated receptor (PPAR) that can induce fluid retention and weight gain through unclear mechanisms. To test a proposed role for the epithelial sodium channel ENaC in thiazolidinedione-induced fluid retention, we used mice with conditionally inactivated ENaC in the collecting duct (Scnn1a^loxloxCre mice). In control mice, rosiglitazone did not alter plasma aldosterone levels or protein expression of ENaC subunits in the kidney, but did increase body weight, plasma volume, and the fluid content of abdominal fat pads, and decreased hematocrit. Scnn1a^loxloxCre mice provided functional evidence for blunted Na⁺ uptake in the collecting duct, but still exhibited rosiglitazone-induced fluid retention. Moreover, treatment with rosiglitazone or pioglitazone did not significantly alter the open probability or number of ENaC channels per patch in isolated, split-open cortical collecting ducts of wild-type mice. Finally, patch-clamp studies in primary mouse inner medullary collecting duct cells did not detect ENaC activity but did detect a nonselective cation channel upregulated by pioglitazone. These data argue against a primary and critical role of ENaC in thiazolidinedione-induced fluid retention.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673