Angiotensin II activates Akt/protein kinase B by an arachidonic acid/redox‐dependent pathway and independent of phosphoinositide 3‐kinase

Angiotensin II (Ang II) exerts contractile and trophic effects in glomerular mesangial cells (MCs). One potential downstream target of Ang II is the protein kinase Akt/protein kinase B (PKB). We investigated the effect of Ang II on Akt/PKB activity in MCs. Ang II causes rapid activation of Akt/PKB (5–10 min) but delayed activation of phosphoinositide 3‐ki‐nase (PI3‐K) (30 min). Activation of Akt/PKB by Ang II was not abrogated by the PI3‐K inhibitors or by the introduction of a dominant negative PI3‐K, indicating that in MCs, PI3‐K is not an upstream mediator of Akt/PKB activation by Ang II. Incubation of MCs with phospholipase A2 inhibitors also blocked Akt/PKB activation by Ang II. AA mimicked the effect of Ang II. Inhibitors of cyclooxygenase‐, lipoxyogenase‐, and cy‐tochrome P450‐dependent metabolism did not influence AA‐induced Akt/PKB activation. However, the antioxidants N‐acetylcysteine and diphenylene iodo‐nium inhibited both AA‐ and Ang II‐induced Akt/PKB activation. Dominant negative mutant of Akt/PKB or antioxidants, but not the dominant negative form of PI3‐K, inhibited Ang II‐induced protein synthesis and cell hypertrophy. These data provide the first evidence that Ang II induces protein synthesis and hypertrophy in MCs through AA/redox‐dependent pathway and Akt/PKB activation independent of PI3‐K.

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