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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 7

Renin granular content in GPR91+/+ and GPR91–/– mice in vivo.

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Renin granular content in GPR91+/+ and GPR91–/– mice in vivo.
   
(A and...
(A and B) Representative multiphoton fluorescence images of JGA renin content (green) in nondiabetic (A and B) and diabetic (C and D) GPR91+/+ (A and C) and GPR91–/– (B and D) mouse kidneys. The intravascular space (plasma) was labeled using a 70-kDa dextran rhodamine conjugate (red). Scale bar: 20 μm. (E) Summary of changes in JGA renin content in control and in the STZ model of type 1 diabetes (STZ-diabetic; DM) GPR91+/+ and GPR91–/– mice. JGA renin content was calculated based on measuring the area of quinacrine fluorescence (μm2).*P < 0.05, C vs. DM GPR91+/+; ΧP < 0.05, C GPR91+/+ vs. C GPR91–/–; #P < 0.05, DM GPR91+/+ vs. DM GPR91–/– (n = 4 each). (F) Renin immunoblot (green) using control and STZ-diabetic GPR91+/+ and GPR91–/– mouse whole kidney. Four samples are shown for each group. β-actin (red) served as loading control. (G) Summary of changes in whole kidney renin content based on renin immunoblot densitometry. *P < 0.05 C vs. DM GPR91+/+; #P < 0.05 DM GPR91+/+ vs. DM GPR91–/– (n = 4 each).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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