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J. Biol. Chem., Vol. 283, Issue 52, 36599-36607, December 26, 2008

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Paracrine Regulation of the Epithelial Na⁺ Channel in the Mammalian Collecting Duct by Purinergic P2Y₂ Receptor Tone^*

Oleh Pochynyuk¹, Vladislav Bugaj, Timo Rieg, Paul A. Insel, Elena Mironova, Volker Vallon, and James D. Stockand

From the Department of Physiology, University of Texas Health Science Center, San Antoxio, Texas 78229-3900 and the Departments of Medicine and Pharmacology, University of California, San Diego, California 92093

Growing evidence implicates a key role for extracellular nucleotides in cellular regulation, including of ion channels and renal function, but the mechanisms for such actions are inadequately defined. We investigated purinergic regulation of the epithelial Na⁺ channel (ENaC) in mammalian collecting duct. We find that ATP decreases ENaC activity in both mouse and rat collecting duct principal cells. ATP and other nucleotides, including UTP, decrease ENaC activity via apical P2Y₂ receptors. ENaC in collecting ducts isolated from mice lacking this receptor have blunted responses to ATP. P2Y₂ couples to ENaC via PLC; direct activation of PLC mimics ATP action. Tonic regulation of ENaC in the collecting duct occurs via locally released ATP; scavenging endogenous ATP and inhibiting P2 receptors, in the absence of other stimuli, rapidly increases ENaC activity. Moreover, ENaC has greater resting activity in collecting ducts from P2Y₂^-/- mice. Loss of collecting duct P2Y₂ receptors in the knock-out mouse is the primary defect leading to increased ENaC activity based on the ability of direct PLC stimulation to decrease ENaC activity in collecting ducts from P2Y₂^-/- mice in a manner similar to ATP in collecting ducts from wild-type mice. These findings demonstrate that locally released ATP acts in an autocrine/paracrine manner to tonically regulate ENaC in mammalian collecting duct. Loss of this intrinsic regulation leads to ENaC hyperactivity and contributes to hypertension that occurs in P2Y₂ receptor^-/- mice. P2Y₂ receptor activation by nucleotides thus provides physiologically important regulation of ENaC and electrolyte handling in mammalian kidney.

Received for publication, September 15, 2008 , and in revised form, October 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01DK59594 and R01DK70571 (to J. D. S.), R01DK56248 and R01DK28602 (to V. V.), and R01GM66232 (to P. A. I.). This work was also supported by American Heart Association (AHA) Established Investigator Award 0640054N (to J. D. S.), AHA Grant-in-Aid 0655232Y (to V. V.), AHA Fellowship 085062F (to O. P.), German Research Foundation Grants RI1535/3-1 and 3-2 (to T. R.), a National Kidney Foundation Fellowship (to T. R.), and the Research Service of the Department of Veterans Affairs (to V. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: 7703 Floyd Curl Dr., San Antonio TX 78229-3900. Tel.: 210-567-4362; Fax: 210-567-4410; E-mail: pochynyuk{at}uthscsa.edu.

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