DsbA-L attenuates acute aristolochic acid nephropathy via alleviating endoplasmic reticulum stress

Aristolochic acid nephropathy (AAN), a severe kidney disease without effective therapy, develops following exposure to aristolochic acid (AA) through the use of AA-containing herbal remedies. Endoplasmic reticulum (ER) stress can induce persistent oxidative stress and is implicated in the pathogenesis of AAN. Disulfide-bond A oxidoreductase-like protein (DsbA-L), an important antioxidant protein, has been shown to suppress ER stress in cardiomyocytes and adipocytes. However, the effects of DsbA-L on acute AAN and AA-induced ER stress remain unknown. Here, we used DsbA-L knockout mice and human proximal tubular epithelial cells (HK-2) transfected with DsbA-L overexpression plasmid to investigate the role of DsbA-L in AA-induced tubular injury. Results showed that AA administration led to an obvious decline of DsbA-L expression. DsbA-L deficiency further exacerbated the activation of ER stress and ER stress-related oxidative stress, apoptosis, and tubular injury in mice with acute AAN. Meanwhile, the protective effects of 4-phenylbutyric acid (a chemical ER stress inhibitor) on blunting AA-induced upregulation of inflammatory and profibrotic factors were dampened after DsbA-L knockout. In HK-2 cells, DsbA-L overexpression exerted protective effects on processes mentioned above. Furthermore, the ability of DsbA-L to suppress ER stress depended on its localization to the ER, a process that is mediated by the interaction with ER oxidoreductase 1α (Ero1α) involving the glycine residue at position 2 of its N terminus. These data indicate that DsbA-L plays a critical role in suppressing the activation of ER stress in acute AAN, thereby ameliorating AA-induced tubular injury.