Decreased fluid reabsorption in the S2 segment of the proximal tubule of SHR is due to reduced activity of NHE3.

Abstract

We showed that the impaired fluid reabsorption (Jv) in the S2 portion of the proximal tubule (PT) of SHR is due to NADPH oxidase, since inhibition with apocynin (APO) restored normal Jv in SHR. Sodium hydrogen exchange-3 (NHE3) is the major Na+ uptake pathway in PT cells. We tested the hypothesis that NADPH oxidase impairs PT fluid uptake in SHR by blunting NHE3 activity. We measured Jv by in vivo microperfusion in SHR and WKY rats with and without APO for 2 days. PT segments were perfused with artificial proximal tubular fluid containing vehicle or S-1611 (10−5 M), a highly selective inhibitor of NHE3. BP was higher in SHR (SHR: 165±5 vs WKY: 115±5 mmHg, n=10) and was not affected by APO. Jv was 50% lower in PT of SHR compared to WKY (SHR: 1.2±0.3 vs WKY: 2.4±0.3 nl/min/mm, p<0.001, n=6–10 nephrons). Fractional reabsorption in the PT was also lower in SHR. APO completely restored Jv (APO: 2.5±0.3 nl/min/mm) and fractional reabsorption in SHR. S-1611 reduced PT Jv in WKY (Veh: 2.4±0.4 vs S-1611: 1.1±0.2 nl/min/mm, p<0.01, n=7–8) but had no effect on PT Jv in SHR (Veh: 1.2±0.03 vs S-1611: 1.3±0.3 nl/min/mm, ns, n=7–8). APO restored PT NHE3 activity, since S-1611 reduced Jv (SHR + APO: 2.5±0.4 vs SHR + APO + S-1611: 1.0±0.3 nl/min/mm, p<0.01, n=7–8). These results show that NADPH oxidase, not BP per se reduces NHE3 activity and Jv in the S2 segment of the PT in SHR.