| Summary: | Sodium salicylate (SA), a cyclooxygenase inhibitor, has been shown to increase insulin sensitivity and to suppress inflammation in obese patients and animal models. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed in afferent nerve fibers. Cyclooxygenase-derived prostaglandins are involved in the activation and sensitization of TRPV1. This study tested whether the metabolic and renal effects of SA were mediated by the TRPV1 channel. Wild-type (WT) and TRPV1<sup>−/−</sup> mice were fed a Western diet (WD) for 4 months and received SA infusion (120mg/kg/day) or vehicle for the last 4 weeks of WD feeding. SA treatment significantly increased blood pressure in WD-fed TRPV1<sup>−/−</sup> mice (<i>p</i> < 0.05) but not in WD-fed WT mice. Similarly, SA impaired renal blood flow in TRPV1<sup>−/−</sup> mice (<i>p</i> < 0.05) but not in WT mice. SA improved insulin and glucose tolerance in both WT and TRPV1<sup>−/−</sup> mice on WD (all <i>p</i> < 0.05). In addition, SA reduced renal p65 and urinary prostaglandin E2, prostaglandin F1α, and interleukin-6 in both WT and TRPV1<sup>−/−</sup> mice (all <i>p</i> < 0.05). SA decreased urine noradrenaline levels, increased afferent renal nerve activity, and improved baroreflex sensitivity in WT mice (all <i>p</i> < 0.05) but not in TRPV1<sup>−/−</sup> mice. Importantly, SA increased serum creatinine and urine kidney injury molecule-1 levels and decreased the glomerular filtration rate in obese WT mice (all <i>p</i> < 0.05), and these detrimental effects were significantly exacerbated in obese TRPV1<sup>−/−</sup> mice (all <i>p</i> < 0.05). Lastly, SA treatment increased urine albumin levels in TRPV1<sup>−/−</sup> mice (<i>p</i> < 0.05) but not in WT mice. Taken together, SA-elicited metabolic benefits and anti-inflammatory effects are independent of TRPV1, while SA-induced sympathetic suppression is dependent on TRPV1 channels. SA-induced renal dysfunction is dependent on intact TRPV1 channels. These findings suggest that SA needs to be cautiously used in patients with obesity or diabetes, as SA-induced renal dysfunction may be exacerbated due to impaired TRPV1 in obese and diabetic patients.
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