DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Li, Xiaozhou1,2; Pan, Jian1,2; Li, Huiling3; Li, Guangdi4; Liu, Xiangfeng5; Liu, Bohao1,2; He, Zhibiao1,2; Peng, Zhengyu1,2; Zhang, Hongliang1,2; Li, Yijian6; Xiang, Xudong1,2; Chai, Xiangping1,2; Yuan, Yunchang7; Zheng, Peilin8; Liu, Feng9,10; Zhang, Dongshan1,2

2020-09-18

10.1038/s41467-020-18304-z

Nature Communications   影响因子和分区

2041-1723

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. DsbA-L upregulation prevents lipid-induced renal injury in diabetic nephropathy. Here, the authors show that DsbA-L knockout attenuates tubulointerstitial fibrosis in mice, and show that this occurs via activation of Smad3 and p53, which result in modulation of CTGF, a regulator of kidney fibrosis.

SCI

英语

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其他

National Natural Science Foundation of China[81870475][81570646][81770951] ; Key R&D projects in Hunan Province[2018SK21215] ; Excellent Youth Foundation of Hunan Scientific Committee[2017JJ1035] ; Changsha Science and Technology Bureau project[kq1901115]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000573763700001

NATURE RESEARCH

Web of Science

1.Cent South Univ, Xiangya Hosp 2, Dept Emergency Med, Changsha, Hunan, Peoples R China
2.Cent South Univ, Emergency Med & Difficult Dis Inst, Changsha, Hunan, Peoples R China
3.Cent South Univ, Xiangya Hosp 2, Dept Ophthalmol, Changsha, Hunan, Peoples R China
4.Cent South Univ, Xiangya Sch Publ Hlth, Hunan Prov Key Lab Clin Epidemiol, Changsha, Hunan, Peoples R China
5.Cent South Univ, Xiangya Hosp 2, Dept Trauma Ctr, Changsha, Hunan, Peoples R China
6.Cent South Univ, Xiangya Hosp 2, Dept Urinary Surg, Changsha, Hunan, Peoples R China
7.Cent South Univ, Xiangya Hosp 2, Dept Chest Surg, Changsha, Hunan, Peoples R China
8.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Dept Endocrinol,Clin Med Coll 2,Affiliated Hosp 1, Shenzhen, Peoples R China
9.Cent South Univ, Dept Endocrinol & Metab, Metab Syndrome Res Ctr, Changsha, Hunan, Peoples R China
10.Univ Texas San Antonio, Dept Pharmacol, San Antonio, TX USA

Li, Xiaozhou,Pan, Jian,Li, Huiling,et al. DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice[J]. Nature Communications,2020,11(1).

Li, Xiaozhou.,Pan, Jian.,Li, Huiling.,Li, Guangdi.,Liu, Xiangfeng.,...&Zhang, Dongshan.(2020).DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.Nature Communications,11(1).

Li, Xiaozhou,et al."DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice".Nature Communications 11.1(2020).