白藜芦醇通过增殖相关信号通路抑制肾脏中的肌成纤维细胞表型和纤维化形成。
Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in kidneys via proliferation-related signalling pathways.
机构信息
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Zhejiang University School of Medicine, Hangzhou, China.
出版信息
Br J Pharmacol. 2019 Dec;176(24):4745-4759. doi: 10.1111/bph.14842. Epub 2019 Nov 28.
BACKGROUND AND PURPOSE
Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. Previous studies have shown that resveratrol has anti-fibrotic activity, but its potential molecular mechanisms of action are not well understood.
EXPERIMENTAL APPROACH
The anti-fibrotic effects of resveratrol were assayed in a rat model of unilateral ureteral obstruction (UUO) in vivo and in fibroblasts and tubular epithelial cells (TECs) stimulated by TGF-β1 in vitro. Gene and protein expression levels were analysed by PCR, Western blotting, and immunohistochemical staining.
KEY RESULTS
Resveratrol inhibits the myofibroblastic phenotype and fibrosis formation in UUO kidneys by targeting fibroblast-myofibroblast differentiation (FMD) and epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of resveratrol correlated with decreased proliferation of TECs in the interstitium and tubules, resulting in suppressed activity of the proliferation-related signalling pathways, including that of the MAPK, PI3K/Akt, Wnt/β-catenin, and JAK2/STAT3 pathways. Resveratrol treatment suppressed TGF-β1-induced FMD and the expression of the myofibroblastic phenotype in fibroblasts in vitro by antagonizing the activation of proliferation-related signalling. Similarly, TGF-β1-mediated overactivation of the proliferation-related signalling in TECs induced EMT, and the myofibroblastic phenotype was suppressed by resveratrol. The anti-fibrotic and anti-proliferative effects of resveratrol were associated with the inactivation of Smad2/3 signalling and resulted in a partial reversal of FMD and EMT and the inhibition of the myofibroblastic phenotype.
CONCLUSIONS AND IMPLICATIONS
Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in vivo and in vitro via proliferation-related pathways, making it a potential therapeutic agent for preventing renal fibrosis.
背景与目的
肾纤维化是导致终末期肾病的共同途径。先前的研究表明，白藜芦醇具有抗纤维化活性，但它的潜在作用机制尚不清楚。
实验方法
在单侧输尿管梗阻（UUO）大鼠模型中体内和转化生长因子-β1（TGF-β1）刺激的成纤维细胞和肾小管上皮细胞（TECs）体外，测定白藜芦醇的抗纤维化作用。通过 PCR、Western blot 和免疫组织化学染色分析基因和蛋白表达水平。
主要结果
白藜芦醇通过靶向成纤维细胞-肌成纤维细胞分化（FMD）和上皮-间充质转化（EMT）抑制 UUO 肾脏的肌成纤维细胞表型和纤维化形成。白藜芦醇的抗纤维化作用与间质和小管中 TEC 增殖的抑制有关，导致增殖相关信号通路的活性受到抑制，包括 MAPK、PI3K/Akt、Wnt/β-catenin 和 JAK2/STAT3 通路。白藜芦醇治疗通过拮抗增殖相关信号的激活，抑制 TGF-β1 诱导的 FMD 和成纤维细胞中肌成纤维细胞表型的表达。同样，TGF-β1 介导的 TEC 中增殖相关信号的过度激活诱导 EMT，白藜芦醇抑制肌成纤维细胞表型。白藜芦醇的抗纤维化和抗增殖作用与 Smad2/3 信号的失活有关，导致 FMD 和 EMT 的部分逆转以及肌成纤维细胞表型的抑制。
结论和意义
白藜芦醇通过增殖相关通路抑制体内和体外的肌成纤维细胞表型和纤维化形成，使其成为预防肾纤维化的潜在治疗药物。
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