DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Xiaozhou Li, Jian Pan, Huiling Li, Guangdi Li, Xiangfeng Liu, Bohao Liu, Zhibiao He, Zhengyu Peng, Hongliang Zhang, Yijian Li, Xudong Xiang, Xiangping Chai, Yunchang Yuan, Peilin Zheng, Feng Liu and Dongshan Zhang ()
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Xiaozhou Li: Central South University
Jian Pan: Central South University
Huiling Li: Central South University
Guangdi Li: Central South University
Xiangfeng Liu: Central South University
Bohao Liu: Central South University
Zhibiao He: Central South University
Zhengyu Peng: Central South University
Hongliang Zhang: Central South University
Yijian Li: Central South University
Xudong Xiang: Central South University
Xiangping Chai: Central South University
Yunchang Yuan: Central South University
Peilin Zheng: The First Affiliated Hospital of Southern University of Science and Technology
Feng Liu: Central South University
Dongshan Zhang: Central South University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.

Date: 2020
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DOI: 10.1038/s41467-020-18304-z

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