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Overexpression of Angiotensinogen Increases Tubular Apoptosis in Diabetes

Fang Liu^*, Marie-Luise Brezniceanu^*, Chih-Chang Wei^*, Isabelle Chénier^*, Sébastien Sachetelli^*, Shao-Ling Zhang^*, Janos G. Filep, Julie R. Ingelfinger and John S.D. Chan^*

^* Université de Montréal, Centre hospitalier de l’Université de Montréal (CHUM)-Hôtel-Dieu, Research Centre Pavillon Masson, Montreal, Quebec, Canada; Université de Montréal, Maisonneuve-Rosemont Hospital, Research Centre, Montreal, Quebec, Canada; and Harvard Medical School, Massachusetts General Hospital, Pediatric Nephrology Unit, Boston, Massachusetts

Correspondence: John S. D. Chan, Université de Montréal Centre hospitalier de l’Université de Montréal (CHUM)-Hôtel-Dieu, Research Centre Pavillon Masson, 3850 Saint Urbain Street, Montreal, Quebec, Canada H2W 1T8. Phone: 514-890-8000 ext. 15080; Fax: 514-412-7204; E-mail: john.chan{at}umontreal.ca

Received for publication January 19, 2007. Accepted for publication August 17, 2007.

The intrarenal renin-angiotensin system (RAS) plays an important role in the progression of diabetic nephropathy. We have previously reported that mice overexpressing angiotensinogen in renal proximal tubular cells (RPTC) develop hypertension, albuminuria, and renal injury. Here, we investigated whether activation of the intrarenal RAS contributes to apoptosis of RPTC in diabetes. Induction of diabetes with streptozotocin in these transgenic mice led to significant increases in BP, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared with diabetic nontransgenic littermates. Insulin and/or RAS blockers markedly attenuated these changes. Hydralazine prevented hypertension but not albuminuria, RPTC apoptosis, or proapoptotic gene expression. In vitro, high-glucose medium significantly increased apoptosis and caspase-3 activity in rat immortalized RPTC overexpressing angiotensinogen compared with control cells, and these changes were prevented by insulin and/or RAS blockers. In conclusion, intrarenal RAS activation and high glucose may act in concert to increase tubular apoptosis in diabetes, independent of systemic hypertension.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673