Abstract 292: AT2 Receptor Activation Prevents High Sodium-induced Increase in Blood Pressure and Insulin Resistance in Obese Rats

Abstract

High sodium intake is a risk factor for the pathogenesis of hypertension and also implicated in insulin resistance. Recently, renal angiotensin AT2 receptor has been shown to promote natriuresis, especially in obese Zucker rats, a model of insulin resistance with modest high blood pressure. However, the role of AT2 receptor in high sodium-induced hypertension and insulin resistance in obesity is not known. Male obese Zucker rats were treated with AT2 receptor agonist C21 (1mg/kg/day oral) while maintained on either normal sodium (NSD, 0.4%) or high sodium diet (HSD, 4%) for 2-weeks. Telemetry monitoring of blood pressure (BP) demonstrated an increase in systolic blood pressure (SBP) by 20 mm Hg in obese HSD compared to NSD group. This increase in SBP was prevented by C21 in rats placed on HSD, but C21 had no effect on SBP in rats on NSD. The rats on HSD had increase in body weight gain (NSD: 45±8 HSD: 74±5 gm) and kidney weight (HSD: 4.7 ±.09, NSD 2.9±.02 gm); the increases were lowered by C21 treatment in HSD group. Compared to NSD rats, HSD rats had significantly reduced GFR (NSD: 654±82, NSD: 302±89 μl/min) which was modestly improved by C21 treatment in HSD group. C21 treatment did not affect food intake in any of the experimental groups. Interestingly, fasting blood glucose and plasma insulin measured at the end of 2-weeks was significantly increased in HSD compared to NSD (glucose: NSD 94±2, HSD 137±8 mg/dL; insulin: NSD 4.3±.3 HSD 8.5±0.6 ng/ml); the increases in both glucose and insulin were prevented by C21 treatment. Similarly, oral glucose tolerance was impaired in HSD obese rats, and the C21 treatment completely normalized the glucose tolerance in HSD rats. Treatment with C21 did not affect blood glucose, insulin levels and GTT in obese rats on NSD. C21 treatment also modestly reduced the epididymal white adipose tissue weight (eWAT) by 15% in HSD+C21 group. This study clearly demonstrate that long-term AT2R agonist treatment prevents the high sodium-induced increase in blood pressure and insulin resistance in in obese rats indicating a potential role in improving metabolic syndrome.