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

J Clin Invest. 2008 Jul;118(7):2526-34. doi: 10.1172/JCI33293.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Citrates / pharmacology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / urine
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / metabolism
  • Endothelial Cells / metabolism
  • Female
  • Glucose / pharmacology
  • Hyperglycemia / metabolism*
  • Juxtaglomerular Apparatus / drug effects
  • Juxtaglomerular Apparatus / metabolism
  • Kidney / metabolism*
  • Male
  • Malonates / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / metabolism
  • Paracrine Communication / drug effects
  • Paracrine Communication / physiology
  • Rabbits
  • Rats
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Renin / blood
  • Renin / metabolism*
  • Succinic Acid / metabolism
  • Succinic Acid / pharmacology
  • Succinic Acid / urine


  • Citrates
  • GPR91 protein, mouse
  • Malonates
  • Receptors, G-Protein-Coupled
  • Nitric Oxide
  • fluorocitrate
  • malonic acid
  • Succinic Acid
  • Renin
  • Glucose
  • Dinoprostone