Published Online
on March 3, 2003

A more recent version of this article appeared on April 1, 2003

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Submitted on November 22, 2002
Revised on December 27, 2002

Akt Is a Major Downstream Target of PI3-Kinase Involved in Angiotensin II-Induced Proliferation

Céline Dugourd; Marianne Gervais; Pierre Corvol; and Catherine Monnot^*

From INSERM U36, Collège de France, Paris, France.

^* To whom correspondence should be addressed. E-mail: catherine.monnot{at}college-de-france.fr.

Abstract--Different signal transduction cascades have been implicated in angiotensin II (Ang II)-mediated cell growth, such as the extracellular signal-regulated kinase 1/2 (ERK1/2) and the phosphatidylinositol 3-kinase (PI3K) pathways. To identify the downstream targets of PI3K involved in Ang II-induced proliferation, we used both rat aortic smooth muscle (RASM) cells and a CHO cell line stably expressing the rat AT_1A receptor. The ERK1/2 and PI3K pathways are independently activated and implicated in Ang II-mediated DNA synthesis and cell number increase in these 2 cell lines. In addition, a specific inhibitor of Akt inhibited Ang II-induced Akt phosphorylation, DNA synthesis and proliferation in CHO-AT_1A or RASM cells. A dominant-negative mutant of Akt was also found to selectively block Ang II-induced proliferation of CHO-AT_1A cells. To further elucidate the signaling events leading to Akt activation, we used an AT₁ receptor mutant (AT_1AD74E), deficient for Gq protein coupling, and the intracellular calcium chelator BAPTA-AM. Although altered Akt and ERK1/2 activation was observed in the CHO-AT_1AD74E cell line, blockade of intracellular calcium elevation did not affect phosphorylation of these kinases. These results provide the first evidence of a specific and necessary role of Akt in Ang II-induced proliferation through a Gq protein-dependent calcium-independent pathway.

Key words: angiotensin II • muscle, smooth, vascular • kinase • hyperplasia • signal transduction

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