Abstract
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−/− 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−/− mice (p < 0.05) but not in WD-fed WT mice. Similarly, SA impaired renal blood flow in TRPV1−/− mice (p < 0.05) but not in WT mice. SA improved insulin and glucose tolerance in both WT and TRPV1−/− mice on WD (all p < 0.05). In addition, SA reduced renal p65 and urinary prostaglandin E2, prostaglandin F1α, and interleukin-6 in both WT and TRPV1−/− mice (all p < 0.05). SA decreased urine noradrenaline levels, increased afferent renal nerve activity, and improved baroreflex sensitivity in WT mice (all p < 0.05) but not in TRPV1−/− mice. Importantly, SA increased serum creatinine and urine kidney injury molecule-1 levels and decreased the glomerular filtration rate in obese WT mice (all p < 0.05), and these detrimental effects were significantly exacerbated in obese TRPV1−/− mice (all p < 0.05). Lastly, SA treatment increased urine albumin levels in TRPV1−/− mice (p < 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.
Highlights
Cyclooxygenase 2 (COX-2) contributes to the development of obesity and obesityassociated metabolic syndrome [1]
Ambulatory blood pressure was measured by telemetry after the mice had been fed with Western diet (WD) for 16 weeks and treated with SA or vehicle for 4 weeks (Figure 1A)
These results suggest that SA treatment suppressed renal sympathetic nerve activity (RSNA) and improved afferent nerve activity (ARNA), likely through Transient receptor potential vanilloid 1 (TRPV1)
Summary
Cyclooxygenase 2 (COX-2) contributes to the development of obesity and obesityassociated metabolic syndrome [1]. Sodium salicylate (SA), a COX inhibitor, inhibits inflammation and improves insulin sensitivity and hyperleptinemia in obesity. Renal COX-mediated generation of prostanoids is enhanced in metabolic disorders, which may play a counter-regulatory role against renal vasoconstriction induced by elevated renal sympathetic nerve activity (RSNA) in obesity. TRPV1 activation enhances ARNA by inducing the release of substance P (SP) from sensory nerves [11]. Obesity is associated with an increase in RSNA [15,16] and impaired ARNA and baroreflex sensitivity (BRS) [17]. It was reported that COX-2-derived PGE2 increased the release of substance P (SP) from renal pelvic sensory nerves and enhanced ARNA [20]. We investigated whether the TRPV1 channel was involved in the metabolic and renal effects of SA treatment in diet-induced obese mice using TRPV1 gene knockout mice
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