Role of the lactate receptor, GPR81, in renal haemodynamic physiology

Abstract

G protein-coupled receptor 81 (GPR81) is abundantly expressed in adipocytes where activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also found in non-adipose tissue but the receptor’s function here is currently not fully understood. In vivo infusion of specific GPR81 agonist, AZ’5538, has been shown to increase blood pressure (BP). We therefore hypothesised a role for GPR81 in the cardiovascular and renal systems with the aim to examine the in vivo effects of AZ’5538 on renal haemodynamics and to localise expression of the receptor within the kidney and vasculature. Initially, we found expression of Gpr81 mRNA in the whole aorta, mesenteric and renal arteries of C57Bl/6JCrl mice using end point PCR. Then, using RNAscope in situ hybridisation in Gpr81-/- mice and wildtype (WT) littermates we found expression in the kidney medulla, arterioles of the glomerulus and smooth muscle cells of the vasculature. WT and Gpr81-/- mice were terminally anaesthetised, the carotid artery cannulated and renal blood flow (RBF) or perfusion measured by a Doppler ultrasound probes during IV infusion of either AZ’5538 or vehicle. Infusion of AZ’5538 significantly increased BP and reduced HR, RBF and cortical and medullary perfusion. Activation of GPR81 in vivo also decreased glomerular filtration rate with no change in ion excretion.

All of these effects were absent in Gpr81 null mice. Plasma endothelin-1 (ET- 1) was increased in mice treated with AZ’5538 with no change in whole kidney and aorta homogenate levels, suggesting release of ET-1 into the circulation.

Prior treatment with BQ-123 (endothelin-A receptor antagonist) prevented the AZ’5538 mediated blood pressure increase whereas BQ-788 (endothelin-B receptor antagonist) had no effect. We showed Gpr81 expression in vascular smooth muscle, glomerulus and medulla of the mouse kidney. In vivo, GPR81 activation influences cardiorenal haemodynamics in an endothelin-A receptor mediated manner by stimulating circulating ET-1. The sensitivity of the renal circulation to GPR81 activation may become physiologically significant when circulating lactate, the endogenous ligand of GPR81, concentration rises, as can occur in ischemic renal disease.