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Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney
Ildikó Toma, … , Elliott Meer, János Peti-Peterdi
Ildikó Toma, … , Elliott Meer, János Peti-Peterdi
Published June 5, 2008
Citation Information: J Clin Invest. 2008;118(7):2526-2534. https://doi.org/10.1172/JCI33293.
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Research Article Nephrology Article has an altmetric score of 12

Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney

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Abstract

Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein–coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca2+, the production of NO and prostaglandin (PGE2), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.

Authors

Ildikó Toma, Jung Julie Kang, Arnold Sipos, Sarah Vargas, Eric Bansal, Fiona Hanner, Elliott Meer, János Peti-Peterdi

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Figure 6

GPR91 signaling in the vascular endothelium.

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GPR91 signaling in the vascular endothelium.
Succinate- and GPR91-induce...
Succinate- and GPR91-induced endothelial cytosolic Ca2+ [Ca2+]i signaling and NO production were studied using the microperfused mouse afferent arteriole–attached glomerulus preparation and confocal fluorescence microscopy with fluo-4/fura red ratiometric Ca2+ (A) and DAF-FM imaging (B), respectively. Arrows point at glomerulus and afferent arteriole endothelial cells in situ. Scale bar: 20 μm. (C) Summary of the high glucose– (25.5 mM) and succinate- (5 mM) induced normalized changes in endothelial [Ca2+]i and NO production in WT GPR91+/+ or KO GPR91–/– kidney tissue. *P < 0.05, WT (+/+) vs. KO (–/–); n = 6 each. (D) Dose-response relationship of succinate-induced elevations in PGE2 production and release from cultured GENCs, measured using a PGE2 biosensor. Specially engineered biosensor cells, HEK293 cells, expressing the Ca2+-coupled PGE2 receptor EP1 were loaded with fluo-4 and positioned next to GENCs in culture. Effects of succinate on GENC PGE2 production were measured based on the biosensor cell Ca2+ signal, since upon PGE2-binding these biosensor cells produce a Ca2+ response detected by fluorescence imaging. The cyclooxygenase inhibitor indomethacin (50 μM) and EP1 receptor blocker SC-51322 (10 μM) in presence of 5-mM succinate both served as negative controls for PGE2 specificity. Normalized changes in HEK293-EP1 biosensor cell fluo-4 intensity are shown and served as an index of PGE2 release. n = 6 for each dose.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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