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

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 Ca 2+ , the production of NO and prostaglandin (PGE 2 ), 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.

Succinate: a metabolic signal in inflammation

“…NO and PGE2 are produced following SUCNR1 ligation and are classic drivers of renin release, an enzyme involved in regulating blood pressure, and a key component of the reninangiotensin system (RAS). Blocking NO and PGE2 production, using specific inhibitors of endothelial NOS and COX-2 respectively, limited succinate-induced renin release [47]. Furthermore, SDH inhibition following malonate treatment enhanced renin release, possibly as a result of succinate accumulation.…”

Insight into SUCNR1 (GPR91) structure and function

“…The current model remains largely elusive but states that succinate binding to SUCNR1 results in production and release of prostaglandins I 2 and E 2 together with NO, which are vasodilators and crucial paracrine mediators of renin release by the juxtaglomerular apparatus (Robben et al, 2009;Toma et al, 2008). The production of these mediators is thought to be the consequence of [Ca 2+ ] i increase and ERK1/2 phosphorylation (Fig.…”

“…Succinate is a citric acid cycle intermediate that accumulates in mitochondria, cytosol and outside the cell in case of oxygen deprivation due to the imbalance between energy demand and oxygen supply (Feldkamp et al, 2004;Hébert, 2004;Peti-Peterdi et al, 2013;Toma et al, 2008). It activates SUCNR1 signaling pathways for the detection of local stress, including ischemia, hypoxia, toxicity, and hyperglycemia.…”

“…The roles of succinate in blood pressure regulation have been well documented in several in vivo and in vitro studies and are strongly linked to the renin-angiotensin system (RAS) activation in the kidney (He et al, 2004;Pluznick & Caplan, 2015;Sadagopan et al, 2007;Toma et al, 2008). In addition, SUCNR1 mRNA has been detected in different nephron segments such as proximal tubule, distal nephron (He et al, 2004), afferent arteriole, glomerulus (Robben et al, 2009;Toma et al, 2008) and the juxtaglomerular apparatus (JGA), the most important regulatory site of systemic blood pressure (He et al, 2004). SUCNR1 protein is also expressed in cortical collecting duct (CD), inner medullary CD principal cell and in macula densa (MD) cells (Robben et al, 2009;Vargas et al, 2009).…”

“…Since renin is a key component of the renal ability to increase blood pressure in the face of low blood volume (Pluznick, 2013), it is tempting to speculate that succinate may be acting via SUCNR1 to support increases in blood volume (and therefore blood pressure). Contradictions in this model include the reported increase of [Ca 2+ ] i in glomerular endothelial cell line (GENC) by succinate that usually results in an inhibition of renin release (Amaral et al, 2012;Toma et al, 2008). Also, Sucnr1 -/-mice have normal baseline blood pressures, likely due to long-term blood pressure counter-regulatory mechanisms.…”