DsbA-L interacts with VDAC1 in mitochondrion-mediated tubular cell apoptosis and contributes to the progression of acute kidney disease

Background we demonstrated that disulfide-bond A oxidoreductase-like protein (DsbA-L) was involved in the progression of renal fibrosis. However, the precise function of DsbA-L in acute kidney injury (AKI), and the mechanisms involved, have yet to be elucidated. Methods We illustrate the DsbA-L interacted with VDACI by co-IP (co-immunoprecipitation) in vitro and vivo, and found the interaction parts of them by mutation experiment. The above findings were verified by co-localization of them. In addition, we constructed the two model of PT-DsbA-L and VDACI KO mice to verify the function of DsbA-L and VDACI in models of VAN, CLP and I/R-induced AKI. Findings The PT-DsbA-L-KO mice showed amelioration of I/R, VAN-, and CLP-induced AKI progression via the downregulation of VDACI. Finally, we confirmed these changes in signal molecules by examining in HK-2 cells and kidney biopsies taken from patients with ischemic or acute interstitial nephritis (AIN)-induced AKI. Mechanistically, DsbA-L interacted with amino acids 9-13 and 22-27 of VDACI in the mitochondria of BUMPT cells to induce renal cell apoptosis and mitochondrial injury. Interpretation This work suggested that DsbA-L, located in the proximal tubular cells, drives the progression of AKI, by directly upregulating the levels of VDACI.Running Title: The role of DsbA-L in AKI Copyright (C) 2022 The Authors. Published by Elsevier B.V.

Automated summary

DsbA-L plays an important role in acute kidney injury (AKI) by upregulating the levels of VDACI, thereby driving the progression of AKI. The study demonstrates that DsbA-L interacts with specific regions of VDACI in the mitochondria, leading to renal cell apoptosis and mitochondrial injury. The findings are validated through mouse models and analysis of patient samples.