Metformin mediates MicroRNA-21 regulated circulating matrix metalloproteinase-9 in diabetic nephropathy: an in-silico and clinical study

Abstract

Metformin is commonly used as an oral hypoglycaemic agent in type 2 diabetes mellitus (T2DM). MicroRNA-21 is widely studied in diabetic and diabetic nephropathy (DN) patients. Matrix metalloproteinase-9 (MMP9) is involved in extracellular matrix degradation and tissue repair processes. However, the effect of metformin administration on hsa-miR-21-5p and MMP9 has not been evaluated in T2DM and DN patients. The study subjects were divided into three groups (Healthy controls = 36, T2DM = 38, DN = 35). Anthropometric measurements were taken and biochemical tests were carried out on fasting blood samples. Reverse transcriptase PCR was employed for whole blood gene expression analysis of hsa-miR-21-5p and MMP9. Bioinformatics analyses including drug-gene interaction, protein-protein interaction, functional enrichment analyses and co-expression networks were performed. In the present study, MMP9 and hsa-miR-21-5p levels were downregulated and upregulated respectively in T2DM and DN patients when compared with healthy controls. However, in metformin-treated group, a downregulation of hsa-miR-21-5p and upregulation of MMP9 was observed. In-silico analysis revealed the target genes involved in the miR-21 and MMP9 interaction network. Metformin directly targets miR-21 and regulates MMP9 expression in T2DM patients, influencing the pathogenesis of DN. Highlights MMP-9 and hsa-miR-21-5p were downregulated and upregulated respectively in T2DM and DN patients in a Western Indian population. The patients treated with metformin showed downregulation of hsa-miR-21-5p and upregulation of MMP9. In-silico analysis revealed MMP-9 as well as PTEN to be targets of hsa-miR-21-5p. Metformin regulates MMP9 expression in T2DM and DN patient populations through hsa-miR-21-5p.