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Increased Renal Responsiveness to Vasopressin and Enhanced V2 Receptor Signaling in RGS2^–/– Mice

Annie Mercier Zuber^*, Dustin Singer^*, Josef M. Penninger, Bernard C. Rossier^* and Dmitri Firsov^*

^* Département de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland; and Institute of Molecular Biotechnology, Vienna, Austria

Address correspondence to: Dr. Dmitri Firsov, Département de Pharmacologie et de Toxicologie Université de Lausanne, 27, rue du Bugnon, CH-1005 Lausanne, Switzerland. Phone: +41-21-6925406; Fax: +41-21-692-5355; E-mail: dmitri.firsov{at}unil.ch

Received for publication January 9, 2007. Accepted for publication March 16, 2007.

The antidiuretic effect of vasopressin is mediated by V2 receptors (V2R) that are located in kidney connecting tubules and collecting ducts. This study provides evidence that V2R signaling is negatively regulated by regulator of G protein signaling 2 (RGS2), a member of the family of RGS proteins. This study demonstrates that (1) RGS2 expression in the kidney is restricted to the vasopressin-sensitive part of the nephron (thick ascending limb, connecting tubule, and collecting duct); (2) expression of RGS2 is rapidly upregulated by vasopressin; (3) the vasopressin-dependent accumulation of cAMP, the principal messenger of V2R signaling, is significantly higher in collecting ducts that are microdissected from the RGS2^–/– mice compared with their wild-type littermates; and (4) analysis of urine output of mice that were exposed to water restriction followed by acute water loading revealed that RGS2^–/– mice exhibit an increased renal responsiveness to vasopressin. It is proposed that RGS2 is involved in negative feedback regulation of V2R signaling.

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