Ablation of TRPV1 Abolishes Salicylate-Induced Sympathetic Activity Suppression and Exacerbates Salicylate-Induced Renal Dysfunction in Diet-Induced Obesity

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.

Keywords: TRPV1; afferent renal nerve activity; blood pressure; obesity; renal dysfunction; sodium salicylate.

Figure 1

SA treatment-induced hypertension in obese TRPV1^−/− mice. Telemetric recording of ambulatory blood pressure (A) and 24-h mean arterial pressure (MAP) (B) in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 5–6; * p < 0.05 vs. TRPV1^−/− mice treated without SA.

Figure 2

Effects of SA on glucose tolerance and insulin resistance. Area under the curve (AUC) of the insulin tolerance test (A) and glucose tolerance test (B) in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Plasma insulin (C) and leptin (D) levels of WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 6–7; * p < 0.05 vs. isogenic mice treated without SA; ^# p < 0.05 vs. WT mice with the same treatment.

Figure 3

Effects of SA on autonomic nerve activity. (A) Urinary norepinephrine levels of WD-fed WT mice and TRPV1^−/− mice treated with or without SA. (B) Intra-renal pelvic infusion of capsaicin-induced afferent renal nerve activity (ARNA). Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 6–7; * p < 0.05 vs. isogenic mice treated without SA; ^# p < 0.05 vs. WT mice with the same treatment.

Figure 4

Effects of SA treatment on baroreflex sensitivity. Baroreflex sensitivity of heart rate (HR) in response to intravenous injection of sodium nitroprusside (50μg/mL) (A) and phenylephrine (125 μg/mL) (B) in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Baroreflex sensitivity of RSNA in response to intravenous injection of sodium nitroprusside (50 μg/mL) (C) and phenylephrine (125 μg/mL) (D) in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 5–7; * p < 0.05 vs. isogenic mice treated without SA; ^# p < 0.05 vs. WT mice with the same treatment.

Figure 5

Effects of SA on renal blood flow. Peak changes of mean renal cortical blood flow (CBF) (A) and medullary blood flow (MBF) (B) in response to intravenous bolus injections of angiotensin II (Ang II) at doses of 0.5, 2.5, and 12.5 ng/kg in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 5–7; * p < 0.05 vs. isogenic mice treated without SA; ^# p < 0.05 vs. WT mice with the same treatment.

Figure 6

Effects of SA on renal inflammatory markers. Renal p65 binding activity (A), urine PGE2 (B), PGF1α (C), and IL-6 (D) in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 5–7; * p < 0.05 vs. isogenic mice treated without SA; ^# p < 0.05 vs. WT mice with the same treatment.

Figure 7

Effects of SA on renal function. GFR (A), serum creatinine (B), urine Kim-1 (C), and urine albumin (D) in WD-fed WT mice and TRPV1^−/− mice treated with or without SA. Differences among groups were performed by two-way ANOVA analysis followed by the Tukey–Kramer multiple comparison test. Values are mean ± SEM; n = 5–7; * p < 0.05 vs. isogenic mice treated without SA; ^# p < 0.05 vs. WT mice with the same treatment.