Abstract P230: Glucagon-like Peptide-1-induced Increases in Afferent Renal Nerve Activity and Renal Sodium Excretion: Role of Trpv1

Abstract

Glucagon-like peptide 1 (GLP-1), an incretin hormone that has clinically been used to treat type 2 diabetic patients, may cause diuresis and natriuresis. However, the mechanism of GLP-1 effects on the kidney is largely unknown. We test the hypothesis that GLP-1 increases afferent renal nerve activity (ARNA) and renal sodium excretion by activation of the transient receptor potential vanilloid 1 (TRPV1) channels expressed in afferent renal nerves innervating the kidney. Exendin-4 (Ex4, 3*10-7M), a GLP-1 receptor agonist perfused into the left renal pelvis, increased ipsilateral ARNA in wild type (WT) mice when compared to TRPV1-null mutant (TRPV1–/–) mice (ARNA % integrated activity, WT:160±22 vs TRPV1-/-: 109±5, p<0.05). Ex4-induced increases in ARNA in WT mice were abolished by capsazepine, a selective antagonist of TRPV1, or by RP67580, a selective antagonist of the neurokinin 1 (NK1) receptor, but not by calcitonin-gene related peptide (CGRP)8-37, a selective antagonist of the CGRP receptor pre-perfused into the renal pelvis. Ex4 increased substance P (SP) and CGRP release from the renal pelvis isolated from WT but not TRPV1-/- mice. Ex4-induced increases in SP and CGRP in WT mice were prevented by Ex9-39, a GLP-1 receptor antagonist, 2,5-dideoxyadenosine, an adenylate cyclase inhibitor (ACI), and brefeldin A (BFA), an EPAC inhibitor, or attenuated by bisindolylmaleimide I (BIM) , a PKC inhibitor, and H89, a PKA inhibitor. Wortmannin (Wort), a PI3K inhibitor, had no effect on Ex4-induced SP or CGRP release. Acute Ex4 treatment (3ug/kg, i.p.) increased renal sodium excretion in both strains with greater degree of increases in WT compared to TRPV1-/- mice (increased % rate, WT: 160±36 vs. TRPV1-/-: 82±7, p<0.05). Thus, our data show that Ex4 increases ARNA, renal SP and CGRP release, and urinary sodium excretion in WT mice, and these functions of Ex4 are impaired in TRPV1-/- mice. These data indicate that Ex4-induced enhancement of ARNA and natriuresis attributes to, at least in part, activation of TRPV1-positive afferent nerves possibly via stimulating the GLP-1R/cAMP-PKA/PKC-TRPV1/SP pathway.