Swainsonine promotes apoptosis by inhibiting autophagic degradation via impairing lysosomal function in primary renal tubular epithelial cells of rats.

Abstract Swainsonine (SW), an indolizidine alkaloid, is the primary toxicant in locoweeds causing toxicity syndrome in livestock. Current research shows that SW can induce programmed cell death, such as apoptosis and autophagy. However, the relationship and regulatory mechanism of autophagy and apoptosis in SW-mediated cytotoxicity remain unclear. In this study, we investigated the role of autophagy and apoptosis in SW induced cytotoxicity in primary renal tubular epithelial cells (RTECs) of rats, and the effect of SW on lysosomes using Western blotting, transmission electron microscopy, fluorescent microscopy and flow cytometry. The results showed that, SW induced both autophagy and apoptosis, and autophagy reflected its protective role in cells against cellular damage. Activating autophagy by rapamycin (Rapa) inhibited apoptosis, while suppressing autophagy by bafilomycin A1 (Baf A1) greatly enhanced SW-induced apoptosis. In addition, SW treatment suppressed the expression of lysosomal-related proteins, and co-incubation with aloxistatin (E64d) further promoted apoptosis and the accumulation of LC3-II. The above results indicate that SW can cause lysosomal dysfunction, lead to inhibition of autophagy degradation, and ultimately promote apoptosis, which may be the key to the mechanism of SW toxicity.