Role of the renal nerves in regulating GLP‐1 mediated diuresis and natriuresis in rats with heart failure
Authors: Katsurada Kenichi , Sharma Neeru M , Zheng Hong , Liu Xuefei , Nandi Shyam S , Patel Kaushik P 
Published: June 2021

Glucagon‐like peptide‐1 (GLP‐1), an incretin hormone has diuretic and natriuretic effects and its receptor agonist reduces cardiovascular events. In the present study, we evaluated the effect of GLP‐1 on renal nerve activity and its contributions to diuresis and natriuresis in normal and heart failure (HF) rats. HF was induced by ligation of the left coronary artery. Immunohistochemistry for GLP‐1 receptor (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. Basal afferent renal nerve activity (ARNA) was increased in HF compared to normal rats (1.3 ± 0.2* vs. 0.6 ± 0.1 μV·s). GLP‐1 (3μM) infused into left renal pelvis increased ipsilateral ARNA in both normal and HF rats. The change in basal ARNA and the maximum ARNA represented as percent activation by injection of capsaicin (transient receptor potential V1 receptor agonist, 100μM) were higher in HF than in normal rats (ΔARNA 227 ± 27%* vs. 131 ± 26%, and ARNAmax 64.2 ± 3.4%* vs. 45.1 ± 6.6%). Intravenous infusion of GLP‐1 (1μg/kg/min) for 30 min increased renal sympathetic nerve activity (RSNA) in both normal and HF rats. The change in basal RSNA was higher in HF than in normal rats (132 ± 29%* vs. 69.7± 16.1%). After cutting the distal end of the renal nerve to eliminate the afferent signal, increase in efferent renal nerve activity (ERNA) during intravenous infusion of GLP‐1 was diminished compared with the increase in total RSNA in normal rat (17.0 ± 9.0%* vs. 68.1 ± 20.0%). These results suggest that increase in RSNA is partly governed by increase in ARNA response to GLP‐1, and this neural pathway is activated in HF condition. Intravenous infusion of GLP‐1 increased renal urine flow and sodium excretion in normal rats and these effects were blunted in HF (urine flow 1577 ± 122* vs. 1981 ± 101 μl/gkw, sodium excretion 221 ± 19* vs. 284 ± 15 μEq/gkw). GLP‐1‐induced diuresis and natriuresis were enhanced by total renal denervation (T‐RDN) with acute surgical cutting of the renal nerves in both normal and HF rats. The degree of diuretic and natriuretic response to GLP‐1 was greater in HF than in normal rats (urine flow 196%* vs. 135%, sodium excretion 186%* vs. 150%). Selective afferent renal denervation (A‐RDN) was performed by bilateral perivascular application of capsaicin (33mM) on the renal nerves. Ten days after A‐RDN, there was an enhanced diuretic and natriuretic response to GLP‐1 in both normal and HF rats. These effects were greater in HF than in normal rats (urine flow 180%* vs. 130%, sodium excretion 169%* vs. 138%). Urine flow and sodium excretion responses to GLP‐1 were not significantly different between T‐RDN and A‐RDN in both groups. Taken together our results indicate that GLP‐1 mediated diuresis and natriuresis are opposed by neural circuitry of afferent and efferent renal nerves. Restoration of diuretic and natriuretic effects of GLP‐1 by RDN have potential therapeutic implication for HF.Support or Funding InformationSupported by NIH grants: PO1‐HL62222 and RO1‐DK114663This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.