Succinate activates the collecting duct renin‐angiotensin system (RAS)

Abstract

The novel metabolic receptor GPR91 controls renin release, the rate-limiting step of RAS, and the renal collecting duct (CD) is the major source of (pro)renin in diabetes. Since the highest GPR91 expression was found in the CD, this study investigated whether succinate, the ligand of GPR91 regulates the local CD RAS. Western blot analysis of succinate-treated M1 cells (CD cell line) showed a dose-dependent, 2–2.5-fold elevation in pERK½, pp38, COX2, renin, prorenin and its receptor [(P)RR]. In WT and GPR91−/− control and STZ-diabetic (DM) mice, CD pERK1/2 (by immunofluorescence) and urinary PGE2 excretion (measured by ELISA) increased 4–20 fold in DM mice and were GPR91-dependent. Medullary (pro)renin and (P)RR protein expression (by immunoblotting) and renin activity in the CD tubular fluid (visualized in vivo using multiphoton microscopy and a fluorogenic renin substrate delivered by renal micropuncture) increased 4–5 fold in WT DM vs. control mice, which was completely abolished in GPR91−/− DM mice. This is the first, direct demonstration of CD renin activity in vivo. Succinate accumulation and GPR91 signaling are novel (patho)physiological regulatory mechanisms that activate the local RAS in the CD via MAP kinases and COX2, PGE2 release, and increased (pro)renin and (P)RR synthesis. Succinate and GPR91 may be important regulators of the local CD RAS in DM and new therapeutic targets in diabetic nephropathy. Supported by: DK74754 and University Kidney Research Organization.