Key result
Angiotensin II activates ERK and cPLA2α in a concentration-dependent manner via AT1, and the balance between these activities determines the biphasic regulation of Na+-HCO3- transport.
The biphasic regulation of Na+-HCO3- transport by Angiotensin II in renal proximal tubules is determined by the balance between AT1-mediated ERK and cPLA2alpha activation.
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Does not alter hypertension or HF management; leaves open clinical translation of AT1-ERK-cPLA2α balance in renal 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.
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Li et al. (2007) studied Renal proximal tubule transport regulation. Angiotensin II vs. Baseline (control fluxes) was evaluated on Na+-HCO3- cotransporter (NBC) activity (p=<0.01). Angiotensin II activates ERK and cPLA2α in a concentration-dependent manner via AT1, and the balance between these activities determines the biphasic regulation of Na+-HCO3- transport.
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