Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Cardiothoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Transplantation. 2019 Oct;103(10):e285-e296. doi: 10.1097/TP.0000000000002864.
The aim of the present study was to investigate the therapeutic potential of metformin in preventing cyclosporine A (CsA)-induced nephrotoxicity.
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.
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).
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.
本研究旨在探讨二甲双胍在预防环孢素 A（CsA）诱导的肾毒性中的治疗潜力。
成年雄性 Sprague-Dawley 大鼠分为三组，分别给予 vehicle、CsA 和 CsA+二甲双胍治疗 4 周，同时给予低钠饮食 1 周。治疗结束时，所有动物均安乐死，采集肾脏、尿液和血液样本进行功能、形态和分子生物学评估。
与 CsA 组相比，二甲双胍可有效预防 CsA 诱导的肾功能障碍，增加肌酐清除率，降低血尿素氮和血清肌酐，减少蛋白尿。形态学上，二甲双胍改善了 CsA 诱导的肾纤维化和动脉、肾小球和近端小管区域的组织塌陷。我们进一步表明，在 CsA 处理的肾脏中，二甲双胍的抗纤维化作用与细胞外信号调节激酶 1/2（ERK1/2）磷酸化的减少有关。
总之，我们的研究揭示了二甲双胍减轻钙调神经磷酸酶抑制剂诱导的肾纤维化的新治疗潜力，这与 MEK/ERK1/2 通路的抑制密切相关。
