ROLE OF ANGIOTENSIN II IN MODULATING FLOW‐DEPENDENT BICARBONATE TRANSPORT IN MOUSE PROXIMAL TUBULES

Abstract

We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na+ and HCO3− absorption and that flow-dependent modulation of proximal tubule bicarbonate reabsorption is due to changes in both NHE3 and H-ATPase activity within the luminal cell membrane. Since Angiotension II is one of the important autocrine hormones that regulate Na+ and HCO3− transport in the proximal tubule, we examined flow-dependent transport in AT1 receptor knockout mice as well as the effect of blockers of AT1, NHE3 and H-ATPase. Mouse proximal tubule S2 segments were microperfused in vitro at flow rates of 5 and 20nl/min in the absence and presence of losartan, EIPA or bafilomycin in the lumen. HCO3− (JHCO3) absorption was significantly lower under both flow rates in AT1 knockout compared to the wild-type mice (see table). Table 1. Flow-dependent Bicarbonate Absorption The fractional increases in JHCO3 in the AT1 KO, the losartan treated, and the wild type mice were 100%, 130% and 94%, the absolute changes were 42.74, 57.76 and 58.5pmole/min/mm and were all comparable. When the components of JHCO3 were assessed using inhibitors, it was found that the fractional increases in JHCO3 were reduced 49% by EIPA plus losartan or by bafilomycin plus losartan in the wild-type mice. We conclude that angiotensin II is not critical to the signal cascade that mediates flow-dependent proton secretion, and that flow impacts transport by both NHE3 and the H-ATPase comparably.