Alpha-lipoic acid attenuates p-cresyl sulfate-induced renal tubular injury through suppression of apoptosis and autophagy in human proximal tubular epithelial cells

Abstract The p-cresyl sulfateaccumulates in kidney disease and may be involved in renal injury. α- Lipoic acid(α-LA) acts as an antioxidant in cell injury. We investigated the effects of α-LA treatment on p-cresyl sulfate-induced renal tubular injury. p-Cresyl sulfateinduced cell death, and increased Bax/Bcl-2, cleaved caspase-3, Beclin-1, and LC3BII/LC3BI in human renal proximal tubular epithelial (HK-2) cells, which was counteracted by α-LA treatment. p-Cresyl sulfate-induced apoptosis was reduced by autophagy inhibitor 3-methyladenine, and p-cresyl sulfateinduced autophagy was reduced by pan-caspase inhibitor Z-VAD-FMK. Moreover, p-cresyl sulfatetreatment increased the expression of ER stress proteins and decreased the expression of baculoviral IAP repeat-containing proteins 6; these effects were prevented by α-LA treatment. Apoptosis and autophagy were associated with the phosphorylation of mitogen-activated protein kinase and nuclear translocation of the nuclear factor-κB p65 subunit. Pretreatment inhibitors of p38 and JNK, and knockdown of ATF4gene reduced apoptosis- and autophagy-related protein expressions in p-cresyl sulfatetreated HK-2 cells. These results demonstrate that α- lipoic acidattenuated p-cresyl sulfate-induced cell death by suppression of apoptosis and autophagy via regulation of ER stress in HK-2 cells.