Rapamycin protects against aristolochic acid nephropathy in mice by potentiating mammalian target of rapamycin-mediated autophagy

Autophagy serves a crucial role in the etiology of kidney diseases, including drug-induced renal impairment, inherited kidney disease, diabetic nephropathy and aristolochic acid nephropathy (AAN) and is, therefore, a potential target for treatment. We previously demonstrated that rapamycin could attenuate AAN in mice; however, the underlying mechanism remains to be elucidated. Therefore, whether the renal protective effect of rapamycin (an autophagy activator) is related to autophagy in aristolochic acid (AA)-treated mice was of particular interest. The pathophysiological roles of rapamycin were investigated in AA-induced nephrotoxicity in mice and the mechanisms of rapamycin action were explored by evaluating the modulation of autophagy in rapamycin-treated mice and cultured renal tubular epithelial cells. Supplementation with rapamycin reversed AA-induced kidney injury in mice and improved AA-induced autophagy damage in vivo and in vitro. Mechanistically, rapamycin inhibited the renal expression of phosphorylated (p-)mammalian target of rapamycin (mTOR) and p-ribosomal S6 protein kinase 1, which in turn activated renal autophagy and decreased apoptosis, probably by removing AA-elicited damaged mitochondria and misfolded proteins. The findings of the present study demonstrated that rapamycin protects against AA-induced nephropathy by activating the mTOR-autophagy axis and suggested that rapamycin may be a promising pharmacological target for the treatment of AAN.