Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis.

Liang A, Wang Y, Woodard LE, Wilson MH, Sharma R, Awasthi YC, Du J, Mitch WE, Cheng J
J Pathol. 2012 228 (4): 448-58

PMID: 22711583 · PMCID: PMC3760987 · DOI:10.1002/path.4067

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.

Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MeSH Terms (17)

Aldehydes Animals Autophagy Cells, Cultured DNA Transposable Elements Fibroblasts Fibrosis Glutathione Transferase Intercellular Junctions Kidney Tubules Lipid Peroxidation Male Mice, Knockout RNA, Messenger Snail Family Transcription Factors Transcription Factors Ureteral Obstruction

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