Received March 9, 2007
Accepted on August 1, 2007

BASIC RESEARCH: Basic Research

Roles of ERK and cPLA₂ in the Angiotensin II-Mediated Biphasic Regulation of Na⁺-HCO₃^- Transport

Yuehong Li ^*, Hideomi Yamada ^*, Yoshihiro Kita , Motoei Kunimi ^*, Shoko Horita ^*, Masashi Suzuki ^*, Yoko Endo ^*, Takao Shimizu , George Seki ^*1, and Toshiro Fujita ^*

*Department of Internal Medicine and Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Nephrology, People’s Hospital, Peking University, Beijing, China

¹ To whom correspondence should be addressed. E-mail: georgeseki-tky{at}umin.ac.jp.

	Abstract

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 (AT_1A)–deficient, and group IVA cytosolic phospholipase A₂ (cPLA₂)–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 AT_1A-deficient mice, suggesting that this occurs through AT_1B. In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA₂ activation because high-concentration Ang II stimulated Na⁺-HCO₃^- cotransporter activity when cPLA₂ activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA₂/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA₂ in a concentration-dependent manner via AT₁, and that the balance between ERK and cPLA₂ activities determines the ultimate response to Ang II in intact proximal tubules.