Renal fibrosis is one of the characteristic features of chronic kidney disease (CKD). Fibrotic change not only impairs the filtration function of the kidney but is also recognized as a marker of end-stage renal disease (ESRD). The epithelial to mesenchymal transition (EMT) is known to play a role in embryonic development and organ formation, but it is getting much attention for its pathological role in the invasion and metastasis of carcinoma. Recently, it has also been reported that EMT plays a role in the formation of fibrosis during chronic inflammation. EMT contribute to the development of the fibrosis in CKD. Moreover, glomerular podocytes and tubular epithelial cells can also undergo mesenchymal transition in CKD.

Hesperetin is a flavonoid present in citrus and is well known for its antioxidant and anti-inflammatory properties. In this study, we investigated the effects of hesperetin on the EMT-elicited podocytes. First, we generated an EMT model by treating transforming growth factor (TGF)-β1, a potent inducer of EMT to the podocytes.

TGF-β1 decreased the expression of epithelial markers such as nephrin, zonula occludens-1 (ZO-1), while it increased the mesenchymal markers, including fibronectin (FN), vimentin, and α-smooth muscle actin (α-SMA) in the podocytes. Hesperetin suppressed EMT-like changes elicited by TGF-β1. Interestingly, hesperetin did not interfere with the Smad signaling-the classical TGF-β signaling-pathway, which was confirmed by the experiment with smad 2/3 −/− podocytes. Instead, hesperetin suppressed EMT-like changes by inhibiting the mTOR pathway-one of the alternative TGF-β signaling pathways.

In conclusion, hesperetin has a protective effect on the TGF-β1 elicited EMT-like changes of podocytes through regulation of mTOR pathway. It could be a good candidate for the suppression of kidney fibrosis in various CKD.

肾纤维化是慢性肾脏病（CKD）的特征之一。纤维化变化不仅损害肾脏的过滤功能，而且被认为是终末期肾脏疾病（ESRD）的标志物。上皮到间充质转变（EMT）在胚胎发育和器官形成中起作用，但由于其在癌的侵袭和转移中的病理作用而受到广泛关注。最近，也有报道说EMT在慢性炎症期间在纤维化的形成中起作用。EMT有助于CKD纤维化的发展。此外，肾小球足细胞和肾小管上皮细胞也可在CKD中经历间质转化。

橙皮素是柑橘类中的类黄酮，以其抗氧化和抗炎特性而闻名。在这项研究中，我们调查了橙皮素对EMT诱导的足细胞的影响。首先，我们通过处理转化生长因子（TGF）-β1（EMT对足细胞的有效诱导剂）生成了EMT模型。

TGF-β1降低了肾上腺素，闭合小带-1（ZO-1）等上皮标志物的表达，同时增加了纤维连接蛋白（FN），波形蛋白和α-平滑肌肌动蛋白（α-SMA）等间充质标志物的表达。足细胞。橙皮素抑制TGF-β1引起的EMT样变化。有趣的是，橙皮素没有干扰Smad信号传导-经典的TGF-β信号传导途径，这在smad 2/3-/-足细胞的实验中得到了证实。相反，橙皮素通过抑制mTOR途径（另一种TGF-β信号途径之一）抑制了EMT样变化。

总之，橙皮素通过调节mTOR途径对TGF-β1引起的足细胞EMT样变化具有保护作用。它可能是抑制各种CKD肾纤维化的良好候选者。