Diabetes, Metabolic Syndrome and Obesity (Dec 2022)
Metformin Ameliorates Epithelial–Mesenchymal Transition of Renal Tubular Epithelial Cells in Diabetes by Increasing Vitamin D Receptor Expression
Abstract
Wenjie Wen,1,2,* Bin Huang,1,2,* Shandong Ye1,2 1Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China (USTC), Department of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 2Department of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shandong Ye, University of Science and Technology of China, No. 96 Jinzhai Road, Hefei, Anhui Province, 230026, People’s Republic of China, Email [email protected]: 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
