Metformin Ameliorates Epithelial–Mesenchymal Transition of Renal Tubular Epithelial Cells in Diabetes by Increasing Vitamin D Receptor Expression

Abstract

Background

Metformin is used as a first-line drug for the treatment of type 2 diabetes. Epithelial–mesenchymal transition (EMT) plays a significant role in the development of renal tubular damage in diabetic kidney disease. However, the underlying mechanisms of EMT in diabetic kidney disease are unclear and how to inhibit this process remains to be explored.

Methods

C57 mice were randomly divided into four groups, including the normal control group (NC group), the Type 2 diabetes group (T2DM group), the metformin group (MET group), and glibenclamide group (GLIB). Fasting blood glucose (FBG), glycated hemoglobin (HbA1c), urinary albumin, RBP, PCX, and creatinine were measured. Renal pathology was observed with HE staining. Molecular mechanism of VDR expression are regulated by metformin through wound healing assay, and Western blot analysis of VDR, Ecad, and SMA in HK2 cells.

Results

In animal experiments, compared with the NC group, the T2DM group showed decreased body weight, increased levels of FBG, HbA1c, UAlb/UCR, URBP/UCR, and UPCX/UCR, decreased levels of VDR protein and mRNA expression in renal tissues (P < 0.05), and significantly increased renal pathological damage in mice in the T2DM group. Compared with the T2DM group, mice in the GLIB and MET groups had higher body weight and lower FBG, HbA1c, UAlb/UCR, URBP/UCR, and UPCX/UCR (P < 0.05). In addition, renal pathological damage was significantly reduced in the MET group compared to the GLIB group. In HK2 cells, high glucose promoted the reduction of VDR and the development of EMT compared to the NC group. In addition, we found that Metformin can up-regulate VDR and inhibit EMT.

Conclusion

Our study shows that the renoprotective effect of metformin is independent of glycemic control and metformin is involved in the progression of EMT by regulating VDR expression.

Keywords:

• type 2 diabetes
• diabetic kidney disease
• metformin
• VDR
• EMT

Ethical Approval

All animal experimental procedures were performed in accordance with the guidelines of the Regulation for the Administration of Affairs Concerning Experimental Animals (Ministry of Science and Technology, China, 1988, revised in March 2017) and approved by the ethics committee of the First Affiliated Hospital of University of Science and Technology of China. This study was also conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals (China).

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval for the version to be published; and agreed to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This study was supported by the local scientific and technological development project guided by the Central Government of China (no. 2017070802D147).