Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway

Abstract

Aims

Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis.

Methods

This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein.

Results

In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was −6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1.

Conclusion

CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Keywords:

• Chlorogenic acid
• diabetic kidney disease
• renal fibrosis
• renal lipid accumulation
• Notch1
• Stat3

Ethics statement

Reporting of animal data in this study followed the recommendations set out in the ARRIVE guidelines.

Author contributions

QQ.Z and XY.Y designed the study and wrote the paper. XY.Y performed most of the experiments and data analysis. D.J, YZ.W and MY.D contributed to data analysis. YW.H, XJ.W, ZM. X, and J.S discussed the results of the study and provided technical support. All authors reviewed the data and approved the final version of the manuscript.

Disclosure statement

The authors have no conflict of interest related to the work described in this article.

Data availability statement

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

Additional information

Funding

This research was funded by the Basic Research Program-young project of Yunnan Province, grant number 202101AU070084; Basic Research project of Yunnan Province, grant number 202301AT070505 and National Natural Science Foundation of China, grant number 81960653.