The mTOR inhibitor everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats
The mTOR inhibitor everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats
复制标题
MTOR抑制剂伊波利莫斯减轻他克莫司诱导的大鼠肾间质纤维化
DOI：
10.1016/j.lfs.2021.120150
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发表时间：
2022-01-01
期刊：
影响因子：
6.1
通讯作者：
Ieiri, Ichiro
中科院分区：
文献类型：
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作者：
Shigematsu, Tomohiro;Tajima, Soichiro;Ieiri, Ichiro
目的：他克莫司是一种广泛使用的免疫抑制剂，用于预防器官移植后的同种异体移植排斥反应，具有肾毒性，会增加肾损伤并伴有肾纤维化的风险。哺乳动物雷帕霉素靶蛋白 (mTOR) 抑制剂依维莫司是一种与他克莫司一起使用的免疫抑制剂。尽管 mTOR 信号传导抑制已被证明具有抗纤维化作用，但依维莫司对抗他克莫司诱导的肾纤维化的功效尚未得到探索。因此，我们评估了依维莫司对他克莫司诱导的肾纤维化的保护作用。 主要方法：为了评估依维莫司对他克莫司诱导的肾纤维化的抗纤维化作用，雄性Wistar大鼠在双侧肾缺血45分钟后皮下注射载体或他克莫司（5 mg/kg每天）和/或依维莫司（0.2 mg/kg每天）2周。还使用大鼠肾成纤维细胞系 (NRK-49F) 评估了依维莫司的抗纤维化作用。 主要发现：他克莫司给药增加了主要促纤维化细胞因子转化生长因子-β (TGF-β) 和成纤维细胞活化标记物 α-平滑肌肌动蛋白 (α-SMA) 的表达，并促进肾皮质中巨噬细胞的浸润，导致大鼠肾间质纤维化。他克莫司增加血清肌酐、血尿素氮、肾损伤分子-1 (KIM-1) 和肾损伤，如肾小管扩张、空泡形成和肾小球萎缩。依维莫司给药可减轻他克莫司诱导的肾纤维化和相关异常。依维莫司通过抑制 mTOR 信号传导强烈抑制 TGF-β 诱导的肾成纤维细胞活化和细胞外基质蛋白表达。意义：我们证明依维莫司可减轻他克莫司诱导的大鼠肾间质纤维化。由于依维莫司对他克莫司引起的肾纤维化具有保护作用，因此与他克莫司联合使用时可能有用。
Aims: Tacrolimus-a widely used immunosuppressant to prevent allograft rejection after organ transplantation-is nephrotoxic, increasing the risk of kidney injury accompanied by kidney fibrosis. The mammalian target of rapamycin (mTOR) inhibitor, everolimus, is an immunosuppressant used together with tacrolimus. Although mTOR signaling inhibition has been demonstrated to exhibit antifibrotic effects, the efficacy of everolimus against tacrolimus-induced kidney fibrosis has not been explored. Therefore, we evaluated the protective effects of everolimus against tacrolimus-induced kidney fibrosis.Main methods: To assess antifibrotic effect of everolimus against tacrolimus-induced kidney fibrosis, male Wistar rats were subcutaneously administered vehicle or tacrolimus (5 mg/kg per day) and/or everolimus (0.2 mg/kg per day) for 2 weeks after bilateral renal ischemia for 45 min. The antifibrotic effect of everolimus was also assessed using rat kidney fibroblast cell line (NRK-49F).Key findings: Tacrolimus administration increased predominant profibrotic cytokine transforming growth factor-beta (TGF-beta) and fibroblast activation marker alpha-smooth muscle actin (alpha-SMA) expression and promoted the infiltration of macrophages in the kidney cortex, resulting in renal interstitial fibrosis in rats. Tacrolimus increased serum creatinine, blood urea nitrogen, kidney injury molecule-1 (KIM-1), and kidney injuries, such as tubular dilation, vacuolization, and glomerular atrophy. Everolimus administration attenuated tacrolimus-induced kidney fibrosis and the associated abnormalities. Everolimus strongly suppressed TGF-beta-induced kidney fibroblast activation and extracellular matrix protein expression by the mTOR signaling inhibition.Significance: We demonstrated that everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats. Owing to its protective effect against tacrolimus-induced kidney fibrosis, everolimus may be useful when used concomitantly with tacrolimus.