Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT
Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT
复制标题
成纤维细胞生长因子 21 通过激活 AKT 负调节 TGF-β-p53-Smad2/3 介导的上皮间质转化，从而减轻糖尿病引起的肾纤维化
DOI：
10.4093/dmj.2018.0235
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发表时间：
2020-02-01
影响因子：
5.9
通讯作者：
Zhang, Chi
中科院分区：
文献类型：
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作者：
Lin, Sundong;Yu, Lechu;Zhang, Chi
背景：糖尿病肾病（DN）的一个特征是肾纤维化，需要上皮细胞向间质细胞转化（EMT）。我们先前的研究表明，成纤维细胞生长因子21（FGF 21）与抑制肾结缔组织生长因子（肾纤维化的关键标志物）表达相关，可预防DN。因此，FGF 21对DN小鼠模型肾纤维化的影响及其机制进行了研究，在本study.Methods：1型糖尿病C57 BL/6 J小鼠腹腔注射多次低剂量链脲佐菌素诱导。然后，在存在匹非德林-α的情况下，用或不用FGF 21治疗糖尿病和非糖尿病小鼠（p53抑制剂）或10-[4 '-（N，N-二乙基氨基）丁基]-2-氯吩恶嗪盐酸盐（10-DEBC）盐酸盐（Akt抑制剂）4个月。DN的诊断依据是肾功能不全、肥大、肾小管间质病变和肾小球硬化伴严重纤维化，所有这些都被FGF 21阻止。FGF 21还通过负性调节转化生长因子β（TGF-β）诱导的Smad 2/3核转位来抑制DN小鼠中糖尿病诱导的肾EMT，Smad 2/3核转位是多种纤维化基因转录所需的。机制研究表明，FGF 21通过抑制其结合蛋白p53的肾活性来减弱Smad 2/3的核转位，所述结合蛋白p53将Smad 2/3携带到核中。此外，匹非他林-α抑制FGF 21诱导的对DN小鼠中肾EMT和随后的肾纤维化的预防作用。结论：FGF 21通过激活Akt/MDM 2/p53信号通路，负性调节TGF-β/Smad 2/3介导的EMT过程，从而抑制肾纤维化。
Background: Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.Methods: Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-alpha (p53 inhibitor) or 10-[4'-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.Results: DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-beta)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-alpha inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).Conclusion: FGF21 prevents renal fibrosis via negative regulation of the TGF-beta/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.