Abstract P436: Intrarenal Ghrelin Receptor Inhibition Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II-induced Hypertension

Abstract

The renal ghrelin receptor (GR) is localized to collecting duct (CD) cells where it increases E Na C-dependent sodium (Na + ) reabsorption. We have previously shown that in uninephrectomized Sprague-Dawley (SD) rats, systemic Ang II infusion induces hypertension after 1 day (129.2 ± 5 vs. 158.2 ± 2.6 mmHg; P<0.01), and this increase is sustained over a 6 day period (191.2 ± 4.0 mmHg; P<0.001). The increase in BP is attenuated with concomitant intrarenal (IR) GR siRNA infusion (F=28.9; P<0.001), but the mechanism is unknown. In this study, we tested whether the reduction in Ang II-induced hypertension in the presence of IR GR siRNA is the result of the prevention of antinatriuresis. Uninephrectomized SD rats (N=33) received a subcutaneous osmotic pump for chronic systemic delivery of Ang II (200 ng/kg/min) or 5% dextrose in water (D 5 W). Rats received IR bolus infusion of D 5 W, GR siRNA (15 μg x 3 over 6 days), or scrambled siRNA (SCR siRNA, 15 μg x 3 over 6 days). Systemic Ang II + SCR siRNA reduced 24 h U Na V from 0.90 ± 0.04 to 0.34 ± 0.08 μmol/min (P<0.001) and increased cumulative Na + balance from 0 to 0.54 mEq Na + (P<0.01) on day 1, with no significant differences for either group for the remainder of the study. IR GR siRNA infusion prevented Ang II-mediated Na + retention (0.86 ± 0.06 vs. 0.87 ± 0.06 μmol/min) and induced a decrease in cumulative Na + balance from 0 to -0.37 ± 0.08 mEq on day 1 with no significant differences for either group for the remainder of the study. At 24 h of Ang II + SCR siRNA infusion, IR GR expression was increased in whole cell kidney (0.55 ± 0.03 vs. 0.91 ± 0.08 DU; P<0.05) and major CD Na + transporter E Na C translocated from intracellular sites to apical plasma membranes to mediate Na + reabsorption (0.34 ± 0.05 vs. 0.51 ± 0.02 DU; P<0.05). In rats receiving IR GR siRNA infusion, however, Ang II failed to recruit E Na C to the apical plasma membranes of CD cells. There was no change in total whole cell E Na C for all conditions. These data demonstrate that chronic inhibition of IR GR activity significantly reduces E Na C-dependent Na + retention, resulting in a negative cumulative Na + balance, thereby preventing Ang II-induced hypertension in rats. Thus, renal GRs represent a novel therapeutic target for the treatment of hypertension and other Na + -retaining states.