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Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Lin Sun^*,, Ping Xie^*, Jun Wada, Naoki Kashihara, Fu-you Liu, Yanan Zhao^*, Deepak Kumar^*, Sumant S. Chugh^||, Farhad R. Danesh^¶ and Yashpal S. Kanwar^*

^* Departments of Pathology & Medicine, Northwestern University, Chicago, Illinois; Department of Nephrology, 2nd Xiangya Hospital Central S. University, Changsha, China; Department of Internal Medicine, Okayama University, and Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan; ^|| Department of Medicine, University of Alabama, Birmingham, Alabama; and ^¶ Department of Medicine, Baylor College of Medicine, Houston, Texas

Correspondence: Dr. Yashpal S. Kanwar, Department of Pathology, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611. Phone: 312-503-0004; Fax: 312-503-0627; E-mail: y-kanwar{at}northwestern.edu

Received for publication March 28, 2008. Accepted for publication May 29, 2008.

The role of tubular injury in diabetic nephropathy is relatively unknown, despite that apoptosis of tubular epithelial cells is commonly observed in human renal biopsies. The GTPase Ras-proximate-1 (Rap1b) is upregulated in the hyperglycemic state and is known to increase B-Raf, an antiapoptotic effector protein. In this study, the effects of high glucose on renal tubular apoptosis and the potential ability for Rap1b to ameliorate these effects were investigated. In the kidneys of diabetic mice, apoptotic tubular cells and dysmorphic mitochondria were observed, Bcl-2 expression was decreased, and Bax expression was increased. Total Rap1b expression was slightly increased, but its associated GTPase activity was significantly decreased. In vitro, high extracellular glucose led to decreased Bcl-2 expression, reduced Rap1b GTPase activity, and increased levels of both Bax and GTPase activating protein in a proximal tubular cell line (HK-2). These changes were accompanied by increased DNA fragmentation, decreased high molecular weight mitochondrial DNA, altered mitochondrial morphology and function, disrupted Bcl-2–Bax and Bcl-2–Rap1b interactions, and reduced cell survival. Overexpression of Rap1b partially prevents these abnormalities. Furthermore, the BH4 domain of Bcl-2 was found to be required for successful protein–protein interaction between Bcl-2 and Rap1b. In summary, these data suggest that Rap1b ameliorates glucose-induced mitochondrial dysfunction in renal tubular cells.

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