Abstract
Advanced glycation end products (AGEs) are formed from amino acids and reducing sugars through nonenzymatic Maillard reaction. AGEs are known to induce oxidative stress, which may cause fibrosis or cancer. In this study, we investigated the protective effect of caffeic acid (CA) on AGE-mediated kidney epithelial to mesenchymal transition (EMT) in human HK-2 cells. Exposure to 100 µg/mL of AGEs by kidney epithelial cells raised the production of reactive oxygen species by 5.2-fold and decreased levels of glutathione. In addition, cardamonin, a β-catenin inhibitor, was used to determine the signaling pathway for β-catenin in which cardamonin inhibited the AGEs-induced translocation of β-catenin into the nucleus, resulting in an inhibition of the EMT process. Similarly, our findings showed that, close to the control level, CA treatment decreased AGE-mediated oxidative stress, loss of E-cadherin expression, and overexpression of α-smooth muscle actin and fibronectin by inactivation of the β-catenin pathway. Furthermore, AGE treatment enhanced the expression of collagen type I (1.99-fold) as well as the activity of metalloproteinases 2 (1.86-fold) and 9 (2.79-fold), but such increase was inhibited by the pretreatment of CA. In conclusion, this study determined the inhibitory effect of CA on AGE-induced β-catenin signaling, which prevented the occurrence of EMT in kidney epithelial cells. This suggests that CA may be a potential target for AGE-induced renal fibrosis. PRACTICAL APPLICATION: Exposure of kidney epithelial cells to advanced glycation end products (AGEs) leads to a rise in reactive oxygen species and a decrease in glutathione, thereby increasing oxidative stress that may cause fibrosis. However, treatment of kidney cells with caffeic acid (CA) prior to their exposure to AGEs lowers oxidative stress and decreases fibrosis. This research reveals the beneficial influence of CA on renal fibrosis in laboratory-cultured kidney cells (in vitro), which makes CA a potential therapeutic target for AGE-induced fibrosis.
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