Abstract 78: Chronic Intrarenal Ghrelin Receptor Antagonism Delays the Onset and Attenuates the Magnitude of High Fat Diet-Induced Hypertension in Dahl Salt-Sensitive Rats

Abstract

Excess weight gain contributes up to 65% of the risk of primary hypertension in developed countries and the increase in blood pressure (BP) in response to high-fat diet (HFD) is preceded by significant reductions in renal tubular sodium (Na + ) excretion. In normal rats, direct renal infusion of ghrelin, the most potent appetite-stimulating hormone in the body, increases distal nephron-dependent Na + reabsorption via activation of ghrelin receptors (GR) in the kidney. The present study seeks to determine the role of intrarenal GR-mediated Na + reabsorption in HFD-induced hypertension. Dahl salt-sensitive rats (DSS) received standard diet (STD, 10% kcal fat, N=6) or HFD (42% kcal fat, N=14) for 6 weeks (WK). Prior to the initiation of the study, all DSS underwent a uninephrectomy and osmotic minipump implantation for chronic renal interstitial (RI) delivery of 5% dextrose in water (D 5 W, 0.25 μL/hr x 28-day) or selective GR antagonist [D-Lys-3]-GHRP-6 (D-LYS, Tocris, IC 50 =0.9 μmol/L, 5 mg over 28-day) into the remaining kidney. At the end of the study, pump patency and security of RI delivery was confirmed via direct visualization. DSS with D 5 W pumps (N=7) demonstrated a significant increase in mean systolic BP (SBP) after 2 WK on HFD (135±4.4 mmHg vs. 118±2.7 mmHg at baseline, *P<0.05) with a mean SBP of 150±3.9 mmHg by WK 6 (***P<0.001 from baseline). However, DSS with D-LYS pumps (N=7) for chronic RI GR antagonism during HFD failed to become hypertensive until WK 4 (134±3.9 mmHg vs. 121±3.3 mmHg at baseline, *P<0.05) and the mean SBP achieved at WK 6 was only 139±3.6 mmHg ( + P<0.05 compared to HFD D 5 W pump rats). DSS fed a STD failed to develop significant hypertension and served as a time control group. HFD rats with D 5 W pumps demonstrated significantly reduced 24-hr urine Na + excretion prior to the onset of hypertension at WK 2 (0.94±0.15 vs. 1.35±0.09 μmol/min at baseline, *P<0.05). The reduction in Na + excretion failed to occur in DSS with a D-LYS pump (1.24 ±0.12 vs. 1.29±0.09 μmol/min at baseline, P=NS) despite exposure to the same HFD and identical weight gain. These results indicate that increased intrarenal GR-mediated Na + reabsorption contributes to the development of HFD-induced hypertension, offering a novel therapeutic target for obesity-induced hypertension.