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J. Biol. Chem., Vol. 279, Issue 20, 21109-21120, May 14, 2004

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A Novel Angiotensin II Type 1 Receptor-associated Protein Induces Cellular Hypertrophy in Rat Vascular Smooth Muscle and Renal Proximal Tubular Cells^*

Deng-Fu Guo, Valerie Tardif, Karin Ghelima, John S. D. Chan, Julie R. Ingelfinger¶, XiangMei Chen||, and Isabelle Chenier

From the Department of Medicine, University of Montreal and Research Center, CHUM-Hotel-Dieu Hospital, Montreal, Quebec H2W 1T8, Canada, ^¶Massachusetts General Hospital, Pediatric Nephrology Unit, Boston, Massachusetts 02114-3117, and ^||Department of Nephrology, General Hospital of the People Liberty Army, 100853 Beijing, China

Angiotensin II stimulates cellular hypertrophy in cultured vascular smooth muscle and renal proximal tubular cells. This effect is believed to be one of earliest morphological changes of heart and renal failure. However, the precise molecular mechanism involved in angiotensin II-induced hypertrophy is poorly understood. In the present study we report the isolation of a novel angiotensin II type 1 receptor-associated protein. It encodes a 531-amino acid protein. Its mRNA is detected in all human tissues examined but highly expressed in the human kidney, pancreas, heart, and human embryonic kidney cells as well as rat vascular smooth muscle and renal proximal tubular cells. Protein synthesis and relative cell size analyzed by flow cytometry studies indicate that overexpression of the novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in cultured rat vascular smooth muscle and renal proximal tubular cells. In contrast, the hypertrophic effects was reversed in renal proximal tubular cell lines expressing the novel gene in the antisense orientation and its dominant negative mutant, which lacks the last 101 amino acids in its carboxyl-terminal tail. The hypertrophic effects are at least in part mediated via protein kinase B activation or cyclin-dependent kinase inhibitor, p27^kip1 protein expression level in vascular smooth muscle, and renal proximal tubular cells. Moreover, angiotensin II could not stimulate cellular hypertrophy in renal proximal tubular cells expressing the novel gene in the antisense orientation and its mutant. These findings may provide new molecular mechanisms to understand hypertrophic agents such as angiotensin II-induced cellular hypertrophy.

Received for publication, February 11, 2004 , and in revised form, February 18, 2004.

^* This work was supported by Canadian Institutes of Health Research Grant MT-14726, the Heart and Stroke Foundation of Canada, the Canadian Foundation for Innovation (to D.-F. G.), the Kidney Foundation of Canada (to J. S. D. C.), and Creative Research Group Fund 30121005 from National Foundation Committee of Natural Science of the People's Republic of China (to X. M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a scholarship from the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed: Dept. of Medicine, University of Montreal and Research Center, CHUM-Hotel-Dieu Hospital, 3850, St.-Urbain, Montreal, Quebec H2W 1T8, Canada. Fax: 514-412-7204; E-mail: guod{at}magellan.umontreal.ca.

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