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GSK3β Promotes Apoptosis after Renal Ischemic Injury

Zhiyong Wang^*, Andrea Havasi^*, Jonathan Gall^*, Ramon Bonegio^*, Zhijian Li, Haiping Mao, John H. Schwartz^* and Steven C. Borkan^*

*Renal Section, Department of Medicine, Boston Medical Center, Boston University, Boston, Massachusetts; and
Department of Nephrology, First Affiliated Hospital, Zhongshan University, GuangZhou, China

Correspondence: Dr. Steven C. Borkan, Evans Biomedical Research Center, Renal Section, Room 546, 650 Albany Street, Boston, MA 02118-2518. Phone: 617-638-7330; Fax: 617-638-7326; E-mail: sborkan{at}bu.edu

Received for publication August 14, 2009. Accepted for publication October 19, 2009.

The mechanism by which the serine-threonine kinase glycogen synthase kinase-3β (GSK3β) affects survival of renal epithelial cells after acute stress is unknown. Using in vitro and in vivo models, we tested the hypothesis that GSK3β promotes Bax-mediated apoptosis, contributing to tubular injury and organ dysfunction after acute renal ischemia. Exposure of renal epithelial cells to metabolic stress activated GSK3β, Bax, and caspase 3 and induced apoptosis. Expression of a constitutively active GSK3β mutant activated Bax and decreased cell survival after metabolic stress. In contrast, pharmacologic inhibition (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione [TDZD-8]) or RNA interference–mediated knockdown of GSK3β promoted cell survival. Furthermore, RNA interference–mediated knockdown of Bax abrogated the cell death induced by constitutively active GSK3β. In a cell-free assay, TDZD-8 inhibited the phosphorylation of a peptide containing the Bax serine¹⁶³ site targeted by stress-activated GSK3β. In rats, TDZD-8 inhibited ischemia-induced activation of GSK3β, Bax, and caspase 3; ameliorated tubular and epithelial cell damage; and significantly protected renal function. Taken together, GSK3β-mediated Bax activation induces apoptosis and tubular damage that contribute to acute ischemic kidney injury.

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				P. J. Nelson and L. Cantley GSK3{beta} Plays Dirty in Acute Kidney Injury J. Am. Soc. Nephrol., February 1, 2010; 21(2): 199 - 200. [Full Text] [PDF]

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