Biphasic Regulation of Na + -HCO 3 − Cotransporter by Angiotensin II Type 1A Receptor

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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 (AT 1A KO). The Na + -HCO 3 − cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with a fluorescent probe, was stimulated by 10 −10 mol/L Ang II but was inhibited by 10 −6 mol/L Ang II in WT. Although valsartan (AT 1 antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT 2 antagonist) did not modify these effects of Ang II. In AT 1A KO, in contrast, this biphasic regulation was lost, and only stimulation of NBC activity by 10 −6 mol/L Ang II was observed. This stimulation was blocked by valsartan but not by PD 123,319. More than 10 −8 mol/L Ang II induced a transient increase in cell Ca 2+ concentrations in WT, which was again blocked by valsartan but not by PD 123,319. However, up to 10 −5 mol/L Ang II did not increase cell Ca 2+ concentrations in AT 1A KO. Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT 1A KO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT 1A KO. These results indicate that AT 1A mediates the biphasic regulation of NBC. Although low-level expression of AT 1B could be responsible for the stimulation by 10 −6 mol/L Ang II in AT 1A KO, no evidence was obtained for AT 2 involvement.