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Metformin Attenuates Cyclosporine A-induced Renal Fibrosis in Rats

Lin, Can-Xiang MSc1,2; Li, Yan MD3; Liang, Shi MD2; Tao, Jun MSc2; Zhang, Li-Sui BSc2; Su, Yang-Fan MD2; Huang, Yun-Xi MSc2; Zhao, Zong-Kai MSc2; Liu, Shan-Ying MD1,4; Zheng, Jun-Meng MD2

doi: 10.1097/TP.0000000000002864
Original Basic Science–General
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Background. The aim of the present study was to investigate the therapeutic potential of metformin in preventing cyclosporine A (CsA)-induced nephrotoxicity.

Methods. Three groups of adult male Sprague-Dawley rats were treated with vehicle, CsA, and CsA + metformin for 4 weeks following 1 week on low sodium diet, respectively. At the end of treatment, all animals were euthanized, and the samples of kidney, urine, and blood were collected for functional, morphological, and molecular biological evaluation.

Results. Metformin effectively prevented CsA-induced renal dysfunction with increased creatinine clearance rate and reduced blood urea nitrogen and serum creatinine, as well as less proteinuria in comparison to the CsA group. Morphologically, metformin ameliorated CsA-induced renal fibrosis and tissue collapse in the areas of arteries, glomeruli, and proximal tubules. We further demonstrated that the antifibrotic effects of metformin in kidneys treated with CsA were associated with decreased phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2).

Conclusions. In conclusion, our study revealed new therapeutic potential of metformin to attenuate calcineurin inhibitor-induced renal fibrosis, which was closely related to the suppression of MEK/ERK1/2 pathway.

1 Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

2 Department of Cardiothoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

3 Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

Received 22 February 2019. Revision received 24 June 2019.

Accepted 25 June 2019.

The work was supported by grants from National Natural Science Foundation of China (81370847 and 81702618).

The authors declare no conflicts of interests.

L.C.X. performed experiments and wrote the article. L.Y. wrote the article. L.S. and S.Y.F. analyzed the data. T.J. and Z.L.S. contributed reagents and provided study materials. H.Y.X. and Z.Z.K. interpreted the results. Z.J.M. designed study and edited the article. L.S.Y. designed the study and performed the experiments. C.-X.L. and Y.L. contributed equally to this work and are the co-first authors. J.-M.Z. and S.-Y.L. are the co-correspondence authors and contributed equally to this work.

Correspondence: Jun-Meng Zheng, MD, Department of Cardiothoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (zhengjm27@mail.sysu.edu.cn);Shan-Ying Liu, MD, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (liushany@mail.sysu.edu.cn).

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