Abstract P001: Diurnal Dysfunction Of The Renal Endothelin System Is Associated With Obesity-induced Hypertension In Rats

Abstract

Loss of endothelin (ET) control of Na + reabsorption results in salt-sensitive hypertension. Diet-induced obesity such as via high fat (HF) diet can produce salt-sensitive hypertension. The goal of this study was to determine if obesity produced by HF diet impairs the renal ET system. Male SD rats were fed either HF (45 Kcal% fat) or normal fat (10 Kcal% fat, NF) diet at 6 weeks of age and for 8 weeks duration. Telemetry transmitters were implanted for systolic blood pressure (SBP) and activity monitoring. During the last 2 weeks of the diet, HF and NF rats were sub-divided into 2 groups to receive an additional high salt (4% NaCl, HS) diet or continue on normal salt (0.3% NaCl, NS) diet. Urine was collected and food and water intakes monitored in 12-hr increments the final 2 days. All groups maintained a diurnal BP pattern. However, rats on HF had significantly higher SBP compared to NF (146 ± 1 vs 138 ± 2 mmHg during the active period, p=0.003, n= 12/group). 12-hr urine volume or Na + excretion values were similar between groups. However, urinary ET-1, a measure of intrarenal ET-1 production, was significantly lower in the HF compared to NF controls (0.92 ± 0.15 vs 1.52 ± 0.09 pg/12hrs, p= 0.0007, n= 12/group). Relative mRNA expression of ET-1 in the renal cortex collected at ZT12 was significantly lower in the HF vs. NF (0.8 ± 0.1 vs 1.3 ± 0.2, p= 0.008, n= 6/group). A similar reduction of ET-1 mRNA was observed in the OM of HF rats. However, there was no change in ET-1 mRNA in the IM of HF rats compared to NF (0.8 ± 0.1 vs 1.0 ± 0.2, p= 0.28, n= 8/group). HS diet led to a further increase in SBP in HF vs the HF/NS group (152 ± 2 vs 147 ± 1 mmHg, p=0.04, n= 8/group) while addition of HS to the NF group showed no significant increase in SBP (145 ± 2 vs 140 ± 3 mmHg, p=0.37 n= 6/group). The NF/HS group had a significant increase in active-time ET-1 excretion compared to NF/NS (4.0 ± 0.4 vs 1.5 ± 0.2 pg/12hrs, p<0.0001, n= 6/group). ET-1 excretion was elevated in the HF/HS vs HF/NS rats (2.6 ± 0.3 vs 1.1 ± 0.1 pg/12hrs, p= 0.02, n= 8/group), but was significantly lower than NF/HS rats (4.0 ± 0.4 pg/12hrs p=0.009). These findings demonstrate that HF diets impair the renal ET-1 system and are consistent with our hypothesis that loss of renal ET-1 contributes to salt-sensitive hypertension in diet-induced obesity.