Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy

Wu,Minmin; Tang,Lili; Chen,Bicheng; Zheng,Jianjian; Dong,Fengquan; Su,Zhen; Lin,Fan

doi:10.3892/etm.2020.8550

Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy

Authors:
- Minmin Wu
- Lili Tang
- Bicheng Chen
- Jianjian Zheng
- Fengquan Dong
- Zhen Su
- Fan Lin
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Affiliations: 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, 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
Published online on: February 25, 2020 https://doi.org/10.3892/etm.2020.8550
Pages: 2887-2894
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chronic aristolochic acid nephropathy (CAAN) is characterized by widespread apoptosis and interstitial fibrosis, which severely impairs kidney function. mTOR is crucial for cell proliferation and protein synthesis. In the present study, the therapeutic effects of blockade of mTOR activity by rapamycin on aristolochic acid nephropathy were investigated. In vitro experiments to determine cell apoptosis and cell cycle alterations caused by aristolochic acid (AA)‑induced injury were conducted on three groups of cells: Untreated control, AAI (treated with aristolochic acid I), and AAI + rapamycin (RMS). In vivo experiments were conducted in a CAAN mouse model. One group of mice was treated with AAI (the CAAN group), while another group was treated with AAI and rapamycin (the treatment group). Kidney function and pathological changes in these mice were assessed by serum creatinine and urea nitrogen analysis. Hematoxylin and eosin staining of renal tissue was performed to evaluate the treatment effects of rapamycin. Western blotting and immunohistochemical staining were used to explore the mechanisms by which rapamycin inhibited cell proliferation, apoptosis and tissue fibrosis. In the in vitro experiments, rapamycin prevented AAI‑induced cell apoptosis and G2/M checkpoint cell cycle arrest. In the in vivo experiments, the treatment group exhibited lower serum creatinine and urea nitrogen, less extensive tubular atrophy and increased amount of glomerulus. Additionally, western blotting and immunohistochemical staining showed that the treatment group exhibited decreased expression levels of fibrosis‑, proliferation‑ and apoptosis‑related proteins compared with the CAAN group. The findings suggest that rapamycin can ameliorate kidney injury induced by AAI via blockade of mTOR, and thus could be a therapeutic strategy for patients with CAAN.

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