Podocyte injury is an early event and core in the development of focal segmental glomerular sclerosis (FSGS) that induces poor prognosis. Epithelial-mesenchymal transition (EMT) as a response of podocyte to injury leads to podocyte depletion and proteinuria. The abnormally reactivated NOTCH pathway may be involved in podocyte EMT. Baicalin, as a natural flavonoid compound, had significant inhibitory activity on tissue fibrosis and tumor cell invasion. However, its potential role and molecular mechanisms to injured podocyte in FSGS are little known. Here we found that baicalin could inhibit podocyte EMT markers expression and cell migration induced by TGF-β1, accompanied by the up-regulated expression of slit diaphragm (SD) proteins and cell-cell adhesion molecule. Further investigation revealed that EMT inhibition of baicalin on injured podocyte is mainly mediated by the reduction of notch1 activation and its downstream Snail expression. Using the adriamycin-induced FSGS model, we determined that baicalin suppresses the Notch1-Snail axis activation in podocytes, relieves glomerulus structural disruption and dysfunction, and reduces proteinuria. Altogether, these findings suggest that baicalin is a novel renoprotective agent against podocyte EMT in FSGS and indicate its underlying mechanism that involves in negative regulation of the Notch1-Snail axis.

中文翻译：

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黄芩苷通过抑制 Notch1-Snail 轴介导的足细胞 EMT 减轻阿霉素诱导的局灶节段性肾小球硬化和蛋白尿

足细胞损伤是局灶节段性肾小球硬化症 (FSGS) 发展的早期事件和核心，可导致预后不良。上皮间质转化 (EMT) 作为足细胞对损伤的反应，导致足细胞耗竭和蛋白尿。异常重新激活的NOTCH通路可能参与足细胞EMT。黄芩苷作为一种天然黄酮类化合物，对组织纤维化和肿瘤细胞侵袭具有显着的抑制活性。然而，其对 FSGS 足细胞损伤的潜在作用和分子机制却鲜为人知。我们发现黄芩苷可以抑制TGF-β1诱导的足细胞EMT标志物表达和细胞迁移，同时上调狭缝隔膜（SD）蛋白和细胞间粘附分子的表达。进一步研究发现黄芩苷对损伤足细胞的EMT抑制主要是通过减少notch1激活及其下游Snail表达来介导的。使用阿霉素诱导的 FSGS 模型，我们确定黄芩苷抑制足细胞中 Notch1-Snail 轴的激活，缓解肾小球结构破坏和功能障碍，并减少蛋白尿。总而言之，这些发现表明黄芩苷是一种针对 FSGS 中足细胞 EMT 的新型肾脏保护剂，并表明其参与 Notch1-Snail 轴负调节的潜在机制。