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.