Hesperetin inhibit EMT in TGF-β treated podocyte by regulation of mTOR pathway

Biochem Biophys Res Commun. 2020 Jul 12;528(1):154-159. doi: 10.1016/j.bbrc.2020.05.087. Epub 2020 May 22.


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.

Keywords: EMT; Hesperetin; Podocyte; TGF-β1; mTOR pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Epithelial-Mesenchymal Transition / drug effects*
  • Hesperidin / chemistry
  • Hesperidin / pharmacology*
  • Humans
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • Podocytes / pathology*
  • Signal Transduction* / drug effects
  • Smad Proteins / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Transforming Growth Factor beta / toxicity*


  • Smad Proteins
  • Transforming Growth Factor beta
  • Hesperidin
  • TOR Serine-Threonine Kinases
  • hesperetin