The Classic Renovascular (Goldblatt) Hypertension (RVHT) is Mediated by Succinate/GPR91 Signaling

Abstract

The novel metabolic receptor GPR91 is key in the activation of the renin‐angiotensin system (RAS). The ligand of GPR91 is the TCA‐cycle intermediate succinate which quickly accumulates in hypoxic tissues. Succinate injection iv in mice causes acute elevations in blood pressure (BP) which is RAS and GPR91 dependent. In the 2‐ kidney, 1‐clip (2K1C) model of RVHT, there is reduced blood flow to the clipped kidney (CK) and hypertension is renin (RAS)‐ dependent. We tested the hypothesis that succinate/GPR91 signaling is involved in the development of RVHT using a novel approach to the 2K1C model as described by Lorenz et al. Wild type (WT) and GPR91 KO mice were either sham operated or a soft cuff was placed on the left renal artery. During 3 weeks, BP was measured daily, and urine and plasma collected weekly. At 3 weeks, systolic BP (SBP) was unchanged in both WT and KO sham groups (WT: 108±2 to 105±14; KO: 104±2 to 91±11 mmHg). SBP increased in cuffed WT from 111±0 to 131±8 mmHg (peaked at week 2 at 148±6 mmHg, P<0.05), but did not change in the cuffed KO (103±13 to 106±9 mmHg). At week 3, kidneys were excised for further analysis. Renin expression increased 3.4±07‐ fold in WT CK, decreased 50% in WT non‐CK (NCK), and was unchanged in the KO CK and NCK. Renal fibrosis in the CK was also improved in GPR91 KO mice. We concluded that GPR91/succinate signaling is a major player in the control of intra‐renal renin (RAS) and BP in RVHT.