TY - JOUR
T1 - DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice
AU - Li, Xiaozhou
AU - Pan, Jian
AU - Li, Huiling
AU - Li, Guangdi
AU - Liu, Xiangfeng
AU - Liu, Bohao
AU - He, Zhibiao
AU - Peng, Zhengyu
AU - Zhang, Hongliang
AU - Li, Yijian
AU - Xiang, Xudong
AU - Chai, Xiangping
AU - Yuan, Yunchang
AU - Zheng, Peilin
AU - Liu, Feng
AU - Zhang, Dongshan
N1 - Funding Information:
This study was supported, in part, by a grant from National Natural Science Foundation of China [81870475, 81570646, and 81770951], Key R & D projects in Hunan Province [2018SK21215], Excellent Youth Foundation of Hunan Scientific Committee [2017JJ1035], and Changsha Science and Technology Bureau project [kq1901115]. We would like to express our gratitude to EditSprings (https://www.editsprings.com/) for the expert linguistic services provided.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-18304-z
DO - 10.1038/s41467-020-18304-z
M3 - Article
C2 - 32948751
AN - SCOPUS:85091252229
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4467
ER -