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Wnt/-Catenin Signaling Modulates Survival of High Glucose–Stressed Mesangial Cells

Chun-Liang Lin^*,,, Jeng-Yi Wang, Yu-Ting Huang^||, Yu-Hsia Kuo^||, Kameswaran Surendran^¶ and Feng-Sheng Wang^,||

Departments of ^* Nephrology and Colorectal Surgery, Chiayi Chang Gung Memorial Hospital, Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Chia-Yi School, Chang Gung Institute of Technology, and ^|| Department of Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan; and ^¶ Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence to: Dr. Feng-Sheng Wang, Department of Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung 833, Taiwan. Phone: +886-7-731-7123, ext. 8876; Fax: +886-7-7338456; E-mail: linchunliang{at}adm.cgmh.org.tw

Received for publication December 20, 2005. Accepted for publication July 24, 2006.

Glomerulosclerosis and diabetic nephropathy are attributable to high glucose induction of mesangial cell apoptosis. Whereas Wnt signaling has been found to regulate renal morphogenesis and pathogenesis, the biologic role of Wnt/-catenin signaling in controlling high glucose–induced mesangial cell apoptosis is not well defined. Herein is reported that Wnt/-catenin signaling is required for protecting glomerular mesangial cells from high glucose–mediated cell apoptosis. High glucose downregulated Wnt4 and Wnt5a expression and the subsequent nuclear translocation of -catenin, whereas it increased glycogen synthase kinase-3 (GSK-3) and caspase-3 activities and apoptosis of glomerular mesangial cells. Suppression of GSK-3 activation or increase in nuclear -catenin by transfection of Wnt4 or Wnt5a or stable -catenin (S33Y) reversed Akt activation and reduced the high glucose–mediated caspase-3 cleavage and cell apoptosis. Pharmacologic inhibition of GSK-3 by recombinant Wnt5a or bromoindirubin-3'-oxime or LiCl increased Akt phosphorylation and -catenin translocation and abrogated high glucose–mediated proapoptotic activities. Exogenous bromoindirubin-3'-oxime treatment reduced phospho-Ser⁹-GSK-3 and -catenin expression and apoptosis of cells adjacent to glomeruli in diabetic kidneys and attenuated urinary protein secretion in diabetic rats. Taken together, mesangial cells responded to high glucose by impairing that canonical Wnt pathway to increase proapoptotic activities. Sustaining Wnt/-catenin signaling is beneficial for promoting survival of mesangial cells that are exposed to high glucose stress.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673