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Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release

Departments of Physiology and Biophysics and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, California

Correspondence: Dr. János Peti-Peterdi, University of Southern California, Zilkha Neurogenetic Institute, 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 July 16, 2008. Accepted for publication December 15, 2008.

Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) are salt sensors and generate paracrine signals that control renal blood flow, glomerular filtration, and release of the prohypertensive hormone renin. We hypothesized that the recently identified succinate receptor GPR91 is present in MD cells and regulates renin release. Using immunohistochemistry, we identified GPR91 in the apical plasma membrane of MD cells. Treatment of MD cells with succinate activated mitogen-activated protein kinases (MAPKs; p38 and extracellular signal–regulated kinases 1/2) and cyclooxygenase 2 (COX-2) and induced the synthesis and release of prostaglandin E₂, a potent vasodilator and classic paracrine mediator of renin release. Using microperfused JGA and real-time confocal fluorescence imaging of quinacrine-labeled renin granules, we detected significant renin release in response to tubular succinate (EC₅₀ 350 µM). Genetic deletion of GPR91 (GPR91^–/– mice) or pharmacologic inhibition of MAPK or COX-2 blocked succinate-induced renin release. Streptozotocin-induced diabetes caused GPR91-dependent upregulation of renal cortical phospho-p38, extracellular signal–regulated kinases 1/2, COX-2, and renin content. Salt depletion for 1 wk increased plasma renin activity seven-fold in wild-type mice but only 3.4-fold in GPR91^–/– mice. In summary, MD cells can sense alterations in local tissue metabolism via accumulation of tubular succinate and GPR91 signaling, which involves the activation of MAPKs, COX-2, and the release of prostaglandin E₂. This mechanism may be integral in the regulation of renin release and activation of the renin-angiotensin system in health and disease.

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