Does Glucagon‐like peptide‐1 induce Diuresis and Natriuresis by Modulating Afferent Renal Nerve Activity?
Authors: Katsurada Kenichi , Sharma Neeru M. , Zheng Hong , Liu Xuefei , Patel Kaushik P. 
Published: June 2021

Cardiovascular outcome studies of Glucagon‐like peptide‐1 receptor (GLP‐1R) agonist suggest that GLP‐1R agonist reduces cardiovascular events and also prevents progression of chronic kidney disease. It has been postulated that GLP‐1 causes diuresis and natriuresis by acting directly on the afferent arterioles or proximal tubules in the kidney. In addition to these direct effects on the end effectors, GLP‐1 may also regulate diuretic and natriuretic effects via the afferent and/or efferent renal nerves. The present study was designed to explore the possible underlying mechanisms for the diuretic and natriuretic actions of GLP‐1 via renal nerves. Immunohistochemistry for GLP‐1R and calcitonin‐gene‐related peptide (CGRP), which is the dominant neurotransmitters for renal afferents, revealed that GLP‐1R was expressed in pelvic wall being adjacent to afferent renal nerves in rats. There was a relatively sparse expression of GLP‐1R in all areas of the cortex of the kidney. GLP‐1 (3μM) infused into left renal pelvis increased ipsilateral afferent renal nerve activity (ARNA) in rats (ΔARNA increased by 40.8% of basal value). This represented 76.6% of the maximum activation of renal afferent nerves as gauged by injection of capsaicin (transient receptor potential V1 receptor agonist, 100μM) into the renal pelvis. Intravenous infusion of GLP‐1 (1μg/kg/min) for 30 min increased renal urine flow and sodium excretion by 7‐fold in rats. These effects were enhanced by total renal denervation (RDN) with acute surgical cutting of the renal nerves (Urine flow rate 86.9±8.2 vs. 59.6±3.3 μl/min/gkw, Sodium excretion 12.6±3.0 vs. 8.6±0.6 μEq/min/gkw, p<0.05, n=9–10). Selective afferent renal nerve denervation (A‐RDN) was performed by bilateral perivascular application of capsaicin (33 mM) on the renal nerves. Ten days after A‐RDN, there was an enhanced diuretic and natriuretic response to GLP‐1 (Urine flow rate 80.0±6.9 vs. 59.6±3.3 μl/min/gkw, Sodium excretion 12.3±1.0 vs. 8.6±0.6 μEq/min/gkw, p<0.05, n=6–10). Urine flow rate and sodium excretion responses to GLP‐1 were not significantly different between RDN and A‐RDN groups. The mean arterial pressure (MAP) and heart rate (HR) were not significantly changed during infusion of GLP‐1 (ΔMAP 3±2 mmHg, ΔHR 7±6, p=ns, n=8). However, the changes of MAP and HR to GLP‐1 were significantly increased by RDN (ΔMAP 9±2 mmHg, ΔHR 23±9, p<0.05, n=8) and A‐RDN (ΔMAP 11±3 mmHg, ΔHR 26±6 bpm, p<0.05, n=4). These changes in MAP and HR to GLP‐1 were not significantly different between the two groups, RDN and A‐RDN. These results indicate that the diuretic and natriuretic effects of GLP‐1 are partly governed via afferent renal nerve activation, by GLP‐1 acting on sensory nerves within the pelvis of the kidney.Support or Funding InformationSupported by NIH grants HL124104 & HL62222.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.