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Biphasic Regulation of Renal Proximal Bicarbonate Absorption by Luminal AT_1A Receptor

Yanan Zheng^*, Shoko Horita^*, Chiaki Hara^*, Motoei Kunimi^*, Hideomi Yamada^*, Takeshi Sugaya, Atsuo Goto^*, Toshiro Fujita^* and George Seki^*

*Department of Internal Medicine, Faculty of Medicine, Tokyo University, Tokyo, Japan; and Discovery Research Laboratory, Tanabe Seiyaku Co, Ltd, Osaka, Japan.

Correspondence to Dr. George Seki, Department of Internal Medicine, Faculty of Medicine, Tokyo University, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-3815-5411 ext. 33004; Fax: 81-3-5800-8806;

ABSTRACT. Angiotensin II (AngII) regulates renal proximal transport in a biphasic way. It has been recently shown that the basolateral type 1A receptor (AT_1A) mediates the biphasic regulation of Na⁺-HCO₃^- cotransporter (NBC) by AngII. However, the receptor subtype(s) responsible for the luminal AngII actions remained to be established. To clarify this issue, the luminal AngII effects in isolated proximal tubules from wild-type (WT) and AT_1A-deficient mice (AT_1A KO) were compared. In WT, the rate of bicarbonate absorption (JHCO₃^-), analyzed with a stop-flow microspectrofluorometric method, was stimulated by 10^-10 mol/L luminal AngII but was inhibited by 10^-6 mol/L luminal AngII. Both stimulatory and inhibitory effects of AngII were completely blocked by valsartan (AT₁ antagonist) but unaffected by PD 123,319 (AT₂ antagonist). In AT_1A KO, in contrast, luminal AngII (10^-10 - 10^-6 mol/L) did not change JHCO₃^-. In WT, 10^-6 mol/L luminal AngII increased cell Ca²⁺ concentrations ([Ca²⁺]_i), which was again blocked by valsartan but not by PD 123,319. However, luminal AngII did not increase [Ca²⁺]_i in AT_1A KO. On the other hand, the addition of arachidonic acid similarly inhibited JHCO₃^- in WT and AT_1A KO. Furthermore, the acute activation of protein kinase C by phorbol 12-myristate 13-acetate similarly stimulated JHCO₃^- in WT and AT1A KO, indicating that the inhibitory and stimulatory pathways necessary for the AngII actions were preserved in AT_1A KO. These results indicate that the luminal AT_1A mediates the biphasic regulation of bicarbonate absorption by luminal AngII, while no evidence was obtained for a role of AT₂. E-mail:georgeseki-tky@uminac.jp

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