Abstract—Although angiotensin (Ang) II is known to regulate renal proximal transport in a biphasic way, the receptor subtype(s) mediating these Ang II effects remained to be established. To clarify this issue, we compared the effects of Ang II in wild-type mice (WT) and Ang II type 1A receptor–deficient mice (AT1AKO). The Na+-HCO3−cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with a fluorescent probe, was stimulated by 10−10mol/L Ang II but was inhibited by 10−6mol/L Ang II in WT. Although valsartan (AT1antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT2antagonist) did not modify these effects of Ang II. In AT1AKO, in contrast, this biphasic regulation was lost, and only stimulation of NBC activity by 10−6mol/L Ang II was observed. This stimulation was blocked by valsartan but not by PD 123,319. More than 10−8mol/L Ang II induced a transient increase in cell Ca2+concentrations in WT, which was again blocked by valsartan but not by PD 123,319. However, up to 10−5mol/L Ang II did not increase cell Ca2+concentrations in AT1AKO. Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT1AKO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT1AKO. These results indicate that AT1Amediates the biphasic regulation of NBC. Although low-level expression of AT1Bcould be responsible for the stimulation by 10−6mol/L Ang II in AT1AKO, no evidence was obtained for AT2involvement.