Abstract P130: Renal Endothelin-1 Contributes to Salt Sensitivity in Male Sprague-Dawley Rats Under High-Fat Conditions

Abstract

Decreased renal medullary endothelin-1 (ET-1) has been attributed to salt sensitive (SS) hypertension. Diet induced obesity is associated with SS, but the role of ET-1 is not clear. Our overarching hypothesis is that high fat (HF) diet produces renal ET-1 dysfunction. Male Sprague-Dawley (SD) rats maintained in 12:12 light:dark conditions were put on either 45 Kcal% fat (high fat, HF) or 10 Kcal% fat (normal fat, NF) diet starting at 6 weeks of age for 8 weeks duration. Half-way through the feeding protocol, rats were implanted with telemetry transmitters for blood pressure (BP) measurement. For the last 2 weeks of feeding, HF and NF groups were divided into 2 subgroups to receive an additional high salt (HS) (4%NaCl) diet or continue on the normal salt (NS) (0.3% NaCl) diet. For the last 3 days of the feeding protocol, rats were put in metabolic cages. Rats on HF diet had an impaired active-time acute natriuretic response after intraperitoneal administration of an acute salt load (ΔUNaV was 605 ± 98 vs 960 ± 59 μEq/12 hrs in the first 12 hours post-load, n= 10, p=0.001). HF diet significantly attenuated ET-1 excretion during the active time period compared to NF (0.92 ±0.15 pg/12hrs vs 1.52 ±0.09, n=12, p=0.0007). Rats on NF given HS, had a significant increase in urinary ET-1 excretion compared to NS (4.34 ±0.35 vs 1.65 ±0.38 pg/12hrs, n=4, p=0.0003). However, HS diet failed to increase ET-1 excretion in rats on HF (1.32 ±0.12 vs 2.56 ±0.29 pg/12 hrs, NS vs HS, respectively, n=6, p=0.10). HF significantly increased systolic BP compared to NF after 6 weeks (141 ±2 vs 134 ±2 mmHg, n=10, p=0.01). HS led to a further increase in active-time systolic BP in the HF group compared to NS (149 ±2 vs 143 ±0.5 mmHg, n=6, p=0.04), while addition of HS to the NF group showed no significant increase in systolic BP (142 ±3 vs 134 ±4 mmHg, n=4, p=0.2) during the active period. Thus, we observed that 1) HF diet impairs the natriuretic response to an acute salt load, that is associated with impaired ET-1 excretion, and 2) HF diet induced SS hypertension in SD rats. Given the importance of ET-1 in the renal response to high salt, these findings are consistent with our hypothesis that reduction in renal endothelin-1 contributes to salt sensitivity in HF male SD rats.