GSK3beta Promotes Apoptosis After Renal Ischemic Injury

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2010 Jan 23

PMID 20093356

Citations 56

Authors

Zhiyong Wang

Andrea Havasi

Jonathan Gall

Ramon Bonegio

Zhijian Li

Haiping Mao

John H Schwartz

Steven C Borkan

Affiliations

Soon will be listed here.

Abstract

The mechanism by which the serine-threonine kinase glycogen synthase kinase-3beta (GSK3beta) affects survival of renal epithelial cells after acute stress is unknown. Using in vitro and in vivo models, we tested the hypothesis that GSK3beta promotes Bax-mediated apoptosis, contributing to tubular injury and organ dysfunction after acute renal ischemia. Exposure of renal epithelial cells to metabolic stress activated GSK3beta, Bax, and caspase 3 and induced apoptosis. Expression of a constitutively active GSK3beta 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 GSK3beta promoted cell survival. Furthermore, RNA interference-mediated knockdown of Bax abrogated the cell death induced by constitutively active GSK3beta. In a cell-free assay, TDZD-8 inhibited the phosphorylation of a peptide containing the Bax serine(163) site targeted by stress-activated GSK3beta. In rats, TDZD-8 inhibited ischemia-induced activation of GSK3beta, Bax, and caspase 3; ameliorated tubular and epithelial cell damage; and significantly protected renal function. Taken together, GSK3beta-mediated Bax activation induces apoptosis and tubular damage that contribute to acute ischemic kidney injury.

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