Abstract 77: Abolished Renal Nerve Protection, Aggravated Renal Functional Impairment, and Elevated Blood Pressure in Response to Inhibition of Cyclooxygenase in Mice Fed a Western Diet: Role of Trpv1

Abstract

Salsalate (sodium salicylate, SA), a cyclooxygenase inhibitor, has been shown to increase insulin sensitivity and to suppress inflammation in obesity and type II diabetes in humans and animals. This study tests the hypothesis that SA (120 mg/kg/day x 4 wks) protects renal nerve function in wild type (WT) but not TRPV1-null mutant (TRPV1 -/- ) mice fed a western diet (WD for 4 months), accompanying with deteriorated renal function and elevated blood pressure in TRPV1 -/- mice fed WD. SA improved glucose tolerance and insulin tolerance in WT-WD-SA and TRPV1-/-WD-SA compared to WT-WD and TRPV1-/-WD groups (P<0.05). Renal pelvis perfusion of capsaicin (CAP, 10 -6 M ), a selective TRPV1 agonist, increased afferent renal nerve activity (ARNA) in WT mice only, with a greater magnitude in WT-WD-SA than in WT-WD mice (P<0.05). Baroreflex (BR) control of renal sympathetic nerve activity (RSNA) in response to IV infusion of sodium nitroprusside (SNP)- or phenylephrine (PE) was improved in WT-WD-SA but impaired in TRPV1-/-WD and TRPV1-/-WD-SA compared to WT-WD mice (P<0.05). SA decreased urinary levels of 6-keto PGF1α (a major metabolite of PGI 2 ) and PGE 2 in TRPV1-/-WD-SA and WT-WD-SA compared to TRPV1-/-WD and WT-WD (P <0.05). SA decreased the glomerular filtration rate (GFR) and increased plasma urea and creatinine levels in both strains fed WD (P <0.05), with greater magnitudes in TRPV1-/-WD-SA than in WT-WD-SA (P <0.05). SA also increased urinary albumin levels in TRPV1-/-WD-SA compared to WT-WD, TRPV1-/-WD, and WT-WD-SA groups (WT-WD 15.2± 2.9; TRPV1-/-WD 22.1±3.5; WT-WD-SA18.4 ±5.0; TRPV1-/-WD-SA 35.9 ± 19.8 ug/24hr, P<0.05). Telemetry mean arterial pressure was not altered by SA in WT-WD-SA, but increased at the night time in TRPV1-/-WD and TRPV1-/-WD-SA compared to corresponding WT controls and at the day time in TRPV1-/-WD-SA compared to TRPV1-/-WD (P<0.05). Thus, inhibition of cyclooxygenase with SA in mice fed WD increases ARNA and sensitivity of BR and BR modulation of RSNA. SA-mediated nerve protective effects are abolished when TRPV1 is ablated, accompanying with exacerbated renal functional impairment and elevated blood pressure. These data may have significant clinical implication for obese and diabetic patients with whom impaired TRPV1 occurs.