Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release

Abstract

Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) are salt sensors and generate paracrine signals that control renal blood flow, glomerular filtration, and release of the prohypertensive hormone renin. We hypothesized that the recently identified succinate receptor GPR91 is present in MD cells and regulates renin release. Using immunohistochemistry, we identified GPR91 in the apical plasma membrane of MD cells. Treatment of MD cells with succinate activated mitogen-activated protein kinases (MAPKs; p38 and extracellular signal-regulated kinases 1/2) and cyclooxygenase 2 (COX-2) and induced the synthesis and release of prostaglandin E 2 , a potent vasodilator and classic paracrine mediator of renin release. Using microperfused JGA and real-time confocal fluorescence imaging of quinacrinelabeled renin granules, we detected significant renin release in response to tubular succinate (EC 50 350 M). Genetic deletion of GPR91 (GPR91 Ϫ/Ϫ mice) or pharmacologic inhibition of MAPK or COX-2 blocked succinate-induced renin release. Streptozotocin-induced diabetes caused GPR91-dependent upregulation of renal cortical phospho-p38, extracellular signal-regulated kinases 1/2, COX-2, and renin content. Salt depletion for 1 wk increased plasma renin activity seven-fold in wild-type mice but only 3.4-fold in GPR91 Ϫ/Ϫ mice. In summary, MD cells can sense alterations in local tissue metabolism via accumulation of tubular succinate and GPR91 signaling, which involves the activation of MAPKs, COX-2, and the release of prostaglandin E 2 . This mechanism may be integral in the regulation of renin release and activation of the renin-angiotensin system in health and disease.

Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

“…The disappearance of quinacrine over time was measured as an index of renin release (26,27). Addition of 10 mM propionate to the bathing solution of JGA/glomeruli from wild-type mice resulted in a decrease in cell-associated quinacrine fluorescence.…”

A novel SCFA receptor, the microbiota, and blood pressure regulation

“…6,7 G-protein coupled receptors of the GPR gene family are also known to act as sensors of metabolites. [8][9][10][11][12] Intriguingly, ligands for these sensory receptors are often generated by physiological processes or metabolic pathways, 1,8,12,13 suggesting that known metabolites or chemicals may have signaling functions beyond their traditional roles. 8,12,13 Furthermore, sensory receptors such as ORs are expressed in a variety of tissues in mice, humans, and other primates, where their functional role has not yet been defined.…”

Insight into SUCNR1 (GPR91) structure and function

“…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). MD cells are known to control renal blood flow, glomerular filtration, and release of renin (Peti-Peterdi & Harris, 2010;Robben et al, 2009;Vargas et al, 2009).…”

“…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). MD cells are known to control renal blood flow, glomerular filtration, and release of renin (Peti-Peterdi & Harris, 2010;Robben et al, 2009;Vargas et al, 2009). …”