Renoprotective effect of Metformin independent of blood sugar control in patients with diabetic kidney disease

Metformin treatment inhibited the epithelial-mesenchymal transition (EMT) process by the upregulation of vitamin D receptor (VDR) seen in renal tubular epithelial cells. VDR overexpression inhibited the EMT process. Mechanistic analysis revealed that metformin inhibits EMT by VDR upregulation in diabetic kidney disease (DKD).

"We found that metformin could reverse EMT by VDR upregulation, thereby inhibiting DKD development. Our findings provide a new rationale for the metformin's renal protective effect," Wenjie Wen from the University of Science and Technology of China in Hefei, People's Republic of China, and colleagues wrote.

Epithelial-mesenchymal transition plays a significant role in developing renal tubular damage in diabetic kidney disease. Metformin is utilized as a first-line drug for type 2 diabetes treatment. However, there is no clarity on the underlying mechanisms of EMT in DKD, and the inhibition of the process remains to be investigated.

C57 mice were divided randomly into four groups, including the type 2 diabetes group (T2DM group), the normal control group (NC group), the glibenclamide group (GLIB), and the metformin group (MET group). Glycated hemoglobin (HbA1c), fasting blood glucose (FBG), retinol-Binding Protein (RBP), creatinine, and podocalyxin (PCX) were measured. Renal pathology was seen with hematoxylin–eosin (HE) staining. The molecular mechanism of VDR expression is regulated by metformin through Western blot analysis of VDR, wound healing assay, Ecad, and SMA (smooth muscle actin) in HK2 cells.

The authors reported the following findings:

• In animal experiments, the T2DM group showed increased levels of HbA1c, FBG, UAlb/UCR, URBP/UCR, and UPCX/UCR, decreased body weight, reduced VDR protein levels and mRNA expression in renal tissues, and significantly increased pathological renal damage in mice in the T2DM group.
• Mice in the MET and GLIB groups had lower HbA1c, FBG, UAlb/UCR, URBP/UCR, and UPCX/UCR and higher body weight than the T2DM group.
• Renal pathological damage was remarkably reduced in the MET group than in the GLIB group.
• In HK2 cells, high glucose promoted VDR reduction and EMT development compared to the NC group. In addition, the authors found that metformin can up-regulate VDR and inhibit EMT.

"Our study reveals that the metformin's renoprotective effect is independent of blood sugar (glycemic) control, and metformin is involved in the EMT progression by regulating VDR expression," the authors concluded.

Reference:

Wen, Wenjie, et al. "Metformin Ameliorates Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells in Diabetes By Increasing Vitamin D Receptor Expression." Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy, vol. 15, 2022, pp. 4001-4010.