DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Xiaozhou Li,Zhibiao He,Xudong Xiang,Xiangping Chai,Yunchang Yuan,Dongshan Zhang,Huiling Li,Guangdi Li,Peilin Zheng,Xiangfeng Liu,Hongliang Zhang,Zhengyu Peng,Jian Pan,Feng Liu,Yijian Li,Bohao Liu

doi:10.1038/s41467-020-18304-z

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.

Highlights

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN)
In an in vitro experiment, we found that renal fibrosis caused by transforming growth factor-β1 (TGF-β1) was ameliorated by DsbA-L short interfering RNA, while in contrast, it was enhanced by the overexpression of DsbA-L
This expression was notably increased in BUMPTs treated with TGF-β1 as well as in the kidneys of ureteral obstruction (UUO) mice and obstructive nephropathy (Ob) patients (Fig. 1a–i)

Summary

Introduction

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). The role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. We found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. The progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was alleviated in PTDsbA-L-KO mice via the activation of Hsp90 /Smad[3] and p53/CTGF axis. 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 /Smad[3] and p53/CTGF axis. The immunohistochemistry result verified that DsbA-L, which had been induced by UUO in PT-DsbA-L-WT mice, tended to be ameliorated in PT-DabA-L-KO tissues, which further verified that tubular DsbA-L was deleted in this conditional KO model (see Fig. 2e)

Methods

Results

Conclusion