GSK3beta promotes apoptosis after renal ischemic injury.
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.
Wang
Zhiyong
Z
Evans Biomedical Research Center, Renal Section, Room 546, 650 Albany Street, Boston, MA 02118-2518, USA.
Havasi
Andrea
A
Gall
Jonathan
J
Bonegio
Ramon
R
Li
Zhijian
Z
Mao
Haiping
H
Schwartz
John H
JH
Borkan
Steven C
SC
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D013830:Thiadiazoles / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D013830:Thiadiazoles; D051028:bcl-2-Associated X Protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3