Inhibitory effect of caffeic acid on advanced glycation end product‐induced renal fibrosis in vitro: A potential therapeutic target

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 ApplicationExposure 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.

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

“…The apoptosis of human mesangial cells (HMCs) and HK-2 cells was accelerated, MDA levels were increased, SOD and GSH were decreased, and mRNA expression levels of RAGE and NF-κB genes were upregulated after AGE-BSA treatment in vitro ( 41 ). Moreover, exposure of HK-2 cells to 100 μg/ml AGE-BSA increased the production of ROS by 5.2 times and reduced GSH level ( 42 ). Lin et al.…”

Autophagy and its therapeutic potential in diabetic nephropathy

“…Inhibiting AGEs/RAGE signaling is reported to restore the disturbed autophagy in glomerular endothelial cells and attenuate DN ( 59 ). It is said that AGEs can enhance the expression of profibrotic molecules linked to EMT and ER stress in the human renal tubular epithelial cell line to gradually render renal fibrosis ( 81 ), which is prevented by the enhancement of autophagy in RTECs ( 54 ). Therefore, the specific role of the AGEs/RAGE axis in DN is worthy of exploring.…”

Epithelial–mesenchymal plasticity in kidney fibrosis

“…Inhibition of GSK‐3β, a downstream mediator of the Wnt/β‐catenin pathway, is another strategy used for protecting the EMT‐mediated kidney fibrosis. Bioactive compounds, such as caffeic acid, epigallocatechin‐3‐gallate (EGCG), AS‐IV, and isoandrographolide have protective effects against EMT‐mediated kidney fibrosis by blocking the GSK‐3β phosphorylation, thereby restoring the GSK‐3β activity to promote β‐catenin degradation (Guan et al, 2022; Jeon et al, 2021; Kanlaya et al, 2022; Yu, Xiao, et al, 2022). EGCG and caffeic acid can also reduce ECM deposition by suppressing MMP‐2 and MMP‐9 activities (Jeon et al, 2021; Kanlaya et al, 2022).…”