Abstract 509: Role of TRPV1 and TRPV4 Channels in the Renal Vasculature

Abstract

Transient receptor potential vanilloid 1 (TRPV1) and vanilloid 4 (TRPV4) cation channels have been recently identified to promote endothelium-dependent relaxation of small mesenteric arteries of mice, with calcium sparklets providing elementary calcium influx through single TRPV4 channels. The role of TRPV1 and TRPV4 in the renal vasculature is largely unknown. We hypothesized that TRPV1 and TRPV4 play an important role in endothelium-dependent vasodilation of renal blood vessels. We performed myography experiments on isolated renal arteries and perfused isolated kidneys of C57BL/6J mice. Isolated mesenteric arteries served as control vessels. The TRPV1 agonist capsaicin relaxed mesenteric arteries with an EC 50 of ~9 nM, but not large renal arteries (EC 50 >10 μM). This relaxation was inhibited by the TRPV1 antagonist capsazepine (10 μM). The capsaicin effect was absent in vessels of TRPV1 knock-out mice. Cytochrome P450 (CYP) 4A- and CYP4F-derived hydroxyeicosatetraenoic acid (20-HETE), which is a proinflammatory mediator of endotoxin-induced acute systemic inflammation, activated TRPV1 channels in patch clamp studies. The TRPV4 agonist GSK1016790A relaxed renal and mesenteric arteries with EC 50 of ~12 nM and 70 nM, respectively. These effects were inhibited by a specific TRPV4 antagonist, AB159908 (10 μM). Capsaicin and GSK1016790A produced vascular dilation in isolated kidneys with EC 50 of ~11 nM and ~2 nM, respectively. The capsaicin effects were absent in kidneys of TRPV1 knock-out mice, whereas the effects of GSK1016790A were also observed in TRPV1 knock-out mice. Our results demonstrate that TRPV4 channels are capable to promote endothelial relaxation in large and small renal arteries, whereas TRPV1 channels play a specific vasodilatory role in small arteries of the kidney. We suggest that specific activation of TRPV1 and TRPV4 may be a novel promising strategy for treatment of sepsis-associated renal vasoconstriction.