Endoplasmic reticulum stress regulates swainsonine-induced the autophagy in renal tubular epithelial cells through UPR signaling pathway.

Swainsonine (SW), the primary toxic component of locoweed, induces toxic response in grazing livestock. The swainsonine induced toxicity is characterized by symptoms including head tremors, ataxia, and limb paralysis. The mechanisms of the toxicity remained to be investigated. The unfolded protein response (UPR) plays a key role in alleviating endoplasmic reticulum stress (ERS) by reducing protein synthesis and promoting the degradation of misfolded proteins. ERS is closely associated with both the UPR and autophagy activation. However, the involvement of the UPR signaling pathway in SW-induced ERS and autophagy remains unclear. In this study, we demonstrate that SW up-regulates the expression of GRP78, XBP1s, LC3-II/I, and ATG5 in both in vitro and in vivo models, suggesting activation of ERS, UPR, and autophagy. To investigate the molecular mechanisms by which the UPR regulates autophagy under ERS in primary rat renal tubular epithelial cells (RTECs), we observed that inhibiting PERK led to increased levels of p62. Inhibition of ATF6 significantly reduced the up-regulation of LC3-II/I, p62, and ATG5. Furthermore, inhibiting IRE1α significantly decreased the expression of LC3-II/I and p62. These findings suggest that PERK and ATF6 regulate autophagy mainly by modulating the expression of autophagy-related genes, while IRE1α likely regulates these genes through the IRE1α-XBP1 pathway. Additionally, autophagy is directly regulated through the IRE1α-JNK signaling pathway.