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

Lin,Fan; Liu,Yunqi; Tang,Lili; Xu,Xiaohui; Zhang,Xueli; Song,Yifan; Chen,Bicheng; Ren,Yeping; Yang,Xiangdong

doi:10.3892/mmr.2021.12134

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

Authors:
- Fan Lin
- Yunqi Liu
- Lili Tang
- Xiaohui Xu
- Xueli Zhang
- Yifan Song
- Bicheng Chen
- Yeping Ren
- Xiangdong Yang
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Affiliations: Department of Nephrology, Qilu Hospital, Shandong University, Jinan, Shandong 250015, P.R. China, Clinical Laboratory, Chinese Medical Hospital of Jining, Jining, Shandong 272037, P.R. China, Department of Nephrology, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: May 5, 2021 https://doi.org/10.3892/mmr.2021.12134
Article Number: 495
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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