Androgens stimulate proximal tubule transport

Background: Disrupting the enzyme cytochrome P4a14 in mice leads to hypertension, which is more severe in male than in female mice and appears to be due to androgen excess. Androgens are known to increase expression of angiotensinogen, but the effect of androgens on proximal tubule transport is unknown. Objective: These studies aimed to determine the effect of androgens on proximal tubule transport. Methods: Proximal tubules from knockout (KO) and wild-type (WT) (SV/129) mice were perfused in vitro. Volume resorption (J(v)) was measured using H-3-methoxy inulin as a volume marker. In separate experiments, male Sprague-Dawley rats were given dihydrotestosterone (DHT) injections IP for 10 days. Proximal tubule transport was measured in this model using in vivo microperfusion. The renal expression of angiotensinogen was measured by Northern analysis, and brush border membrane protein abundance of the sodium-hydrogen exchanger isoform 3 (NHE3) was measured by Western blotting in the control and DHT-treated rats. Results: Mean (SE) J(v) was significantly elevated in proximal tubules from KO mice compared with WT mice (1.11 [0.06] vs 0.7 7 [0.12] nL/min.mm, respectively; P < 0.05). The mean proximal tubule Jv rate was significantly higher in DHT-treated rats than in control rats given vehicle injections (4.57 [0.31] vs 3.31 [0.23] nL/mm.min, respectively; P < 0.01). Luminal perfusion with either enalaprilat or losartan decreased the proximal tubule J(v) rate in DHT-treated rats to a greater degree than in control rats. The DHT-treated rats had higher blood pressures and lower serum angiotensin II concentrations than did the control rats. Conclusion: Results suggest that androgens may directly upregulate the proximal tubule renin-angiotensin system, increase the expression of NHE3, and increase the Jv rate, thereby increasing extracellular volume and blood pressure and secondarily decreasing serum angiotensin II concentrations.