High glucose levels directly triggered the release of renin via a paracrine signaling pathway involving succinate accumulation and activation of the GPR91 receptor in the glomerular endothelium.
The succinate receptor GPR91 provides a mechanistic link between high glucose levels in diabetes and renin-angiotensin system overactivation.
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 et al. (2008) studied Diabetes mellitus. High glucose levels was evaluated on Renin release and activation of GPR91 signaling cascade. High glucose levels directly triggered the release of renin via a paracrine signaling pathway involving succinate accumulation and activation of the GPR91 receptor in the glomerular endothelium.