Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney.
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.
Toma
Ildikó
I
Department of Physiology and Biophysics, University of Southern California, Los Angeles, California 90033, USA.
Kang
Jung Julie
JJ
Sipos
Arnold
A
Vargas
Sarah
S
Bansal
Eric
E
Hanner
Fiona
F
Meer
Elliott
E
Peti-Peterdi
János
J
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002951:Citrates / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000652:urine; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D012083:Renin / Q000097:blood / Q000378:metabolism*; D019802:Succinic Acid / Q000378:metabolism / Q000494:pharmacology / Q000652:urine
D002951:Citrates; C531499:GPR91 protein, mouse; D008314:Malonates; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; C007744:fluorocitrate; C030290:malonic acid; D019802:Succinic Acid; D012083:Renin; D005947:Glucose; D015232:Dinoprostone