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

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 A 2 (PLA 2 ) 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 A 2 (cPLA 2 ␣)-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 ϩ -HCO 3 Ϫ cotransporter activity are both AT 1 -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 cPLA 2 ␣ activation because high-concentration Ang II stimulated Na ϩ -HCO 3 Ϫ cotransporter activity when cPLA 2 ␣ activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA 2 ␣/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA 2 ␣ in a concentration-dependent manner via AT 1 , and that the balance between ERK and cPLA 2 ␣ activities determines the ultimate response to Ang II in intact proximal tubules.

Roles of MEK/ERK Pathway in Vascular and Renal Tubular Actions of Angiotensin II

“…On the other hand, the MEK inhibitor PD9805 abolished only the stimulatory effect of Ang II, leaving the inhibitory effect of Ang II unaffected. These results indicate that the ERK pathway mediates only the stimulatory effect of Ang II in intact proximal tubules [12]. Further analysis showed that the inhibitory effect of Ang II is independent of the ERK pathway, but dependent on the group IVA cytosolic PLA 2 (cPLA2 ) activity.…”

“…The recent study has shown that the ERK pathway is also involved in the Ang IImediated stimulation of sodium absorption from renal proximal tubules [12]. However, Ang II seems to utilize quite different signaling mechanisms to activate ERK in VSMCs and renal tubules.…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…Although controversial data have been reported concerning the receptor subtype(s) that are responsible for the biphasic effects of ANG II on proximal tubular transport [87,88], some studies have clearly indicated that both luminal and basolateral AT1A receptors mediate the biphasic effects of Ang II on proximal transport [89][90][91]. It has been shown that at physiological concentrations, binding between ANG II and the AT1 receptor induces the rapid activation of PLC, which results in the release of IP3 and DAG, which are themselves involved in slightly increasing [Ca 2+ ]i by mobilizing Ca 2+ from intracellular storage and by activating PKC, respectively [92][93][94].…”

“…It has been shown that at physiological concentrations, binding between ANG II and the AT1 receptor induces the rapid activation of PLC, which results in the release of IP3 and DAG, which are themselves involved in slightly increasing [Ca 2+ ]i by mobilizing Ca 2+ from intracellular storage and by activating PKC, respectively [92][93][94]. These processes may ultimately result in the activation of ERK [71,83,90]. At high concentrations, ANG II induces the activation of the phospholipase A2 (PLA2)/arachidonic acid/5,6-epoxyeicosatrienoic acid (EET) pathway and/or the NO/ cGMP pathway and the mobilization of intracellular Ca 2+ , also through mechanisms involving the AT1 receptor [83,86,95,96].…”

“…On the other hand, region B of the exchanger binds to Ca 2+ /CaM only when there has been a higher increase in [Ca 2+ ] i (induced by various hormonal concentrations, as indicated in Figure 6), and under these conditions, binding inhibits the NHE. This scheme is based on theoretical studies [81,90] and on experimental studies using site-directed mutagenesis [18] it is known that the biphasic hormonal effects on the calcium-dependent regulation of NHE3 are dependent on calmodulin (CaM). Briefly, the data indicate that CaM binds to NHE1 at two sites in the cytosolic tail: region A (a high affinity site that contains residues 637-657) and region B (a low affinity site that is comprised of residues 657-700) [26].…”