GSTA3 Attenuates Renal Interstitial Fibrosis by Inhibiting TGF-Beta-Induced Tubular Epithelial-Mesenchymal Transition and Fibronectin Expression.
Tubular epithelial-mesenchymal transition (EMT) has been widely accepted as the underlying mechanisms of renal interstitial fibrosis (RIF). The production of reactive oxygen species (ROS) plays a vital role in tubular EMT process. The purpose of this study was to investigate the involved molecular mechanisms in TGF-beta-induced EMT and identify the potential role of glutathione S-transferase alpha 3 (GSTA3) in this process. The iTRAQ screening was performed to identify protein alterations of the rats underwent unilateral-ureteral obstruction (UUO). Protein expression of GSTA3 in patients with obstructive nephropathy and UUO rats was detected by immunohistochemistry. Protein and mRNA expression of GSTA3 in UUO rats and NRK-52E cells were determined by Western blot and RT-PCR. siRNA and overexpression plasmid were transfected specifically to assess the role of GSTA3 in RIF. The generation of ROS was measured by dichlorofluorescein fluorescence analysis. GSTA3 protein and mRNA expression was significantly reduced in UUO rats. Immunohistochemical analysis revealed that GSTA3 expression was reduced in renal cortex in UUO rats and patients with obstructive nephropathy. Treating with TGF-β1 down-regulated GSTA3 expression in NRK-52E cells, which have been found to be correlated with the decreased expression in E-cadherin and megalin and increased expression in α-smooth muscle actin. Furthermore, knocking down GSTA3 in NRK-52 cells led to increased production of ROS and tubular EMT, whereas overexpressing GSTA3 ameliorated ROS production and prevented the occurrence of tubular EMT. GSTA3 plays a protective role against tubular EMT in renal fibrosis, suggesting GSTA3 is a potential therapeutic target for RIF.
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China, 410078.|Division of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China, 510120.
Yun
Y
Xiao
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China, 410078.
Jishi
J
Liu
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China, 410078.
Yu
Y
Peng
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China, 410078.
Xuan
X
Xiong
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China, 410078.
Ling
L
Huang
Division of Digestive Medicine, Xiangya Hospital, Central South University, Changsha, China, 410078.
Huixiang
H
Yang
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, United States of America.
Jian
J
Zhang
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, China, 410078.|State Key Laboratory of Medical Genetics of China, Central South University, Changsha, China, 410078.
Lijian
L
Tao
D000818:Animals; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics
C067625:FN1 protein, human; D005353:Fibronectins; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D005982:Glutathione Transferase; C495975:glutathione S-transferase A3-3, human