Abstract 224: Differential Actions of Angiotensin II on Proximal Tubule Transport

Abstract

Studies with the proximal tubule-specific angiotensin type 1 receptor (AT 1 R) knockout mouse have shown that the proximal tubule (PT) contributes to Ang II-induced hypertension. Ang II levels in the PT fluid are 100- to 1000-fold higher than in plasma, yet the function of the AT 1 -Rs on the luminal side of the PT is unclear. Moreover, hemodynamic actions of Ang II that raise the filtration fraction and the peritubular fluid uptake forces also stimulate PT fluid uptake. We tested the effects of Ang II and AT 1 -Rs on PT fluid uptake in rats. Ang II (200 ng/kg/min) delivered for 2 weeks increased MAP (Con: 95±9 vs Ang II: 140±5 mmHg, p<0.001), single nephron GFR (snGFR)(Con: 36±3 vs Ang II: 43±3, p<0.05) and absolute proximal reabsorption (APR) (Con: 20±3 vs Ang II: 34.5±6.5 nl/min, p<0.01), measured by free flow collections in the S2 segments of the PT in Sprague Dawley (SD) rats. These effects were normalized by acute reduction of MAP via a supra-renal aortic clamp. In a separate group of Munich Wistar Frömter (MWF) rats, which have surface glomeruli, Ang II increased snGFR and APR in the S1 segment (Con: 19±4 vs AngII: 44±5 nl/min, p<0.01; +125±9 %) substantially more than in the S2 segment (Con: 25±6 vs Ang II 37±7 nl/min, p<0.01; +48±6 %). In microperfusion and recollection experiments, in which snGFR was controlled, fluid uptake (Jv) in the PT of SD rats was reduced dose-dependently by Ang II delivered directly into the lumen of S2 segments. Ang II (10 -9 M) at physiological levels reduced Jv by 60±7%. This effect on Jv was blocked by co-perfusion of an AT 1 R blocker. Ang II (10 -9 M), microperfused directly into the S2 reduced Jv in MWF rats as well by 44±5%. Ang II in cultured PT cells at higher concentrations (10 -7 to 10 -9 M) also reduced 22 Na + uptake by 20-35%. In conclusion, enhanced PT fluid reabsorption by Ang II is due to hemodynamic enhancement that likely entails peritubular fluid uptake primarily in the S1 segment. However, luminal Ang II acting on AT 1 -Rs in the S1 and S2 segments of the PT reduces fluid uptake. This effect could be overridden by the hemodynamic effect of systemic Ang II to increase reabsorption especially in the S1 segment.