Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis.
Glutathione transferase isozyme A4 (GSTA4) exhibits high catalytic efficiency to metabolize 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product that has been implicated in the pathogenesis of various chronic diseases. We investigated the role of 4-HNE in the mechanisms of unilateral ureteral obstruction (UUO)-induced fibrosis and its modulation by GSTA4-4 in a mouse model. Our data indicate that after UUO, accumulation of 4-HNE and its adducts were increased in renal tissues, with a concomitant decrease in the expression of GSTA4-4 in mice. As compared to wild-type (WT) mice, UUO caused an increased expression of fibroblast markers in the interstitium of GSTA4 KO mice. Additionally, increased autophagy and tubular cell damage were more severe in UUO-treated GSTA4 KO mice than in WT mice. Furthermore, GSK-3β phosphorylation and expression of Snail, a regulator of E-cadherin and Occludin, was found to be significantly higher in UUO-inflicted GSTA4 KO mice. GSTA4 over-expression prevented 4-HNE-induced autophagy activation, tubular cell damage and Snail nuclear translocation in vitro. The effects of long-term expression of GSTA4 in restoration of UUO-induced damage in mice with the GSTA4 inducible transposon system indicated that release of obstruction after 3 days of UUO resulted in the attenuation of interstitial SMAα and collagen I expression. This transposon-delivered GSTA4 expression also suppressed UUO-induced loss of tubular cell junction markers and autophagy activation. Together, these results indicate that 4-HNE significantly contributes to the mechanisms of tubule injury and fibrosis and that these effects can be inhibited by the enhanced expression of GSTA4-4.
Nephrology Division, Baylor College of Medicine, Houston, TX, USA; Department of Orthopaedics, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Anlin
A
Liang
Yun
Y
Wang
Lauren E
LE
Woodard
Matthew H
MH
Wilson
Rajendra
R
Sharma
Yogesh C
YC
Awasthi
Jie
J
Du
William E
WE
Mitch
Jizhong
J
Cheng
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology; D002478:Cells, Cultured; D004251:DNA Transposable Elements; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis / Q000201:enzymology / Q000473:pathology; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D007365:Intercellular Junctions / Q000201:enzymology / Q000473:pathology; D007684:Kidney Tubules / Q000201:enzymology* / Q000473:pathology*; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology*
D000447:Aldehydes; D004251:DNA Transposable Elements; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C529117:GSTA4-4 protein, mouse; D005982:Glutathione Transferase; C027576:4-hydroxy-2-nonenal