DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.
Xiaozhou LiJian PanHuiling LiGuangdi LiXiangfeng LiuBohao LiuZhibiao HeZhengyu PengHongliang ZhangYijian LiXudong XiangXiangping ChaiYunchang YuanPeilin ZhengFeng LiuDongshan ZhangPublished in: Nature communications (2020)
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.
Keyphrases
- induced apoptosis
- diabetic nephropathy
- growth factor
- low dose
- high glucose
- cell cycle arrest
- epithelial mesenchymal transition
- heat shock protein
- transforming growth factor
- oxidative stress
- heat stress
- cell proliferation
- heat shock
- signaling pathway
- endoplasmic reticulum stress
- type diabetes
- liver failure
- high dose
- intensive care unit
- endothelial cells
- heart failure
- adipose tissue
- skeletal muscle
- cerebral ischemia
- metabolic syndrome
- extracellular matrix
- acute ischemic stroke
- fatty acid
- poor prognosis
- mechanical ventilation
- acute respiratory distress syndrome