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Connexin 30 Deficiency Impairs Renal Tubular ATP Release and Pressure Natriuresis

Arnold Sipos^*,, Sarah L. Vargas^*, Ildikó Toma^*, Fiona Hanner^*, Klaus Willecke and János Peti-Peterdi^*,

*Departments of Physiology and Biophysics and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California;
Hungarian Academy of Sciences, Research Group for Pediatrics and Nephrology, and Institute of Pathophysiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary; and
Institute of Genetics, Division of Molecular Genetics, University of Bonn, Bonn, Germany

Correspondence: Dr. János Peti-Peterdi, Department of Physiology and Biophysics and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, 1501 San Pablo Street, ZNI 335, Los Angeles, CA 90033. Phone: (323) 442-4337; Fax: (323) 442-4466; E-mail: petipete{at}usc.edu

Received for publication October 22, 2008. Accepted for publication March 17, 2009.

In the renal tubule, ATP is an important regulator of salt and water reabsorption, but the mechanism of ATP release is unknown. Several connexin (Cx) isoforms form mechanosensitive, ATP-permeable hemichannels. We localized Cx30 to the nonjunctional apical membrane of cells in the distal nephron and tested whether Cx30 participates in physiologically important release of ATP. We dissected, partially split open, and microperfused cortical collecting ducts from wild-type and Cx30-deficient mice in vitro. We used PC12 cells as ATP biosensors by loading them with Fluo-4/Fura Red to measure cytosolic calcium and positioning them in direct contact with the apical surface of either intercalated or principal cells. ATP biosensor responses, triggered by increased tubular flow or by bath hypotonicity, were approximately three-fold greater when positioned next to intercalated cells than next to principal cells. In addition, these responses did not occur in preparations from Cx30-deficient mice or with purinergic receptor blockade. After inducing step increases in mean arterial pressure by ligating the distal aorta followed by the mesenteric and celiac arteries, urine output increased 4.2-fold in wild-type mice compared with 2.6-fold in Cx30-deficient mice, and urinary Na⁺ excretion increased 5.2-fold in wild-type mice compared with 2.8-fold in Cx30-deficient mice. Furthermore, Cx30-deficient mice developed endothelial sodium channel–dependent, salt-sensitive elevations in mean arterial pressure. Taken together, we suggest that mechanosensitive Cx30 hemichannels have an integral role in pressure natriuresis by releasing ATP into the tubular fluid, which inhibits salt and water reabsorption.

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