Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+-HCO3(-) transport.
Regulation of renal proximal transport by angiotensin II (Ang II) is biphasic: low concentrations (picomolar to nanomolar) stimulate reabsorption, but higher concentrations (nanomolar to micromolar) inhibit reabsorption. Traditionally, the stimulatory effect has been attributed to activation of protein kinase C and/or a decrease in intracellular cAMP, whereas the inhibitory action has been attributed to the activation of phospholipase A2 (PLA2) and the subsequent release of arachidonic acid. The Ang II receptor subtype responsible for these effects and the intracellular signaling pathways involved are not completely understood. We isolated proximal tubules from wild-type, Ang II type 1A receptor (AT1A)-deficient, and group IVA cytosolic phospholipase A2 (cPLA2alpha)-deficient mice, and compared their responses to Ang II. In wild-type mice, we found that the stimulatory and inhibitory effects of Ang II on Na+-HCO3(-) cotransporter activity are both AT1-mediated but that ERK activation only plays a role in the former. The stimulatory effect of Ang II was also observed in AT1A-deficient mice, suggesting that this occurs through AT1B. In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA2alpha activation because high-concentration Ang II stimulated Na+-HCO3(-) cotransporter activity when cPLA2alpha activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA2alpha/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA2alpha in a concentration-dependent manner via AT1, and that the balance between ERK and cPLA2alpha activities determines the ultimate response to Ang II in intact proximal tubules.
Li
Yuehong
Y
Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Yamada
Hideomi
H
Kita
Yoshihiro
Y
Kunimi
Motoei
M
Horita
Shoko
S
Suzuki
Masashi
M
Endo
Yoko
Y
Shimizu
Takao
T
Seki
George
G
Fujita
Toshiro
T
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D017693:Sodium Bicarbonate; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2