Biphasic regulation of Na+-HCO3- cotransporter by angiotensin II type 1A receptor.
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+-HCO3- 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 (AT1 antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT2 antagonist) did not modify these effects of Ang II. In AT1A 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 Ca2+ 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 Ca2+ concentrations in AT1A 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 AT1A KO, no evidence was obtained for AT2 involvement.
Horita
Shoko
S
Department of Internal Medicine, Faculty of Medicine, Tokyo University, Tokyo, Japan.
Zheng
Yanan
Y
Hara
Chiaki
C
Yamada
Hideomi
H
Kunimi
Motoei
M
Taniguchi
Shigeo
S
Uwatoko
Shu
S
Sugaya
Takeshi
T
Goto
Atsuo
A
Fujita
Toshiro
T
Seki
George
G
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D005456:Fluorescent Dyes; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D001639:Bicarbonates; D020536:Enzyme Activators; D005456:Fluorescent Dyes; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D027982:Sodium-Bicarbonate Symporters; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D016718:Arachidonic Acid; D000068756:Valsartan; D012964:Sodium; D014633:Valine; D002118:Calcium