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Metformin inhibits TGF-beta 1-induced MCP-1 expression through BAMBI-mediated suppression of MEK/ERK1/2 signalling

Diefei Liang^1,2, Zijiao Song^1,2, Weiwen Liang¹

¹Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

Nephrology (Carlton, Vic.)

|June 24, 2018

Abstract

Aims:

Metformin is a biguanide derivative widely used for the treatment of type 2 diabetes mellitus. Recent evidence demonstrates that this anti-hyperglycaemic drug exerts renal protective effects, yet the mechanisms remain poorly understood. monocyte chemoattractant protein 1 (MCP-1) has been recognized as a key mediator of renal fibrosis in chronic kidney diseases, including diabetic nephropathy. This study aimed to investigate the effects of metformin on transforming growth factor beta 1 (TGF-β1)-induced MCP-1 expression and the underlying mechanisms in rat renal tubular epithelial cells.

Methods:

Rat renal tubular epithelial cell line NRK-52E cells were stimulated with TGF-β1 and/or metformin. The messenger RNA (mRNA) of MCP-1 and bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) was evaluated by real-time quantitative polymerase chain reaction. MCP-1 protein was measured by enzyme linked immunosorbent assay (ELISA). Total and phosphorylated extracellular signal-regulated kinases 1/2 (ERK1/2) was evaluated by western blot. Down- and upregulation of BAMBI were achieved by RNA interference targeting BAMBI and lentiviral vector-mediated overexpression of the BAMBI gene, respectively. Cell viability was analysed using Cell Counting Kit 8 (CCK-8) reagents.

Results:

Stimulation with TGF-β1 resulted in the increased expression of MCP-1 and decreased expression of BAMBI in NRK-52E cells. Metformin inhibited the expression of MCP-1 in NRK-52E cells. Pretreatment with metformin suppressed upregulation of MCP-1 and downregulation of BAMBI, as well as phosphorylation of ERK1/2 induced by TGF-β1. U0126, a specific inhibitor for mitogen-activated and extracellular signal-regulated kinase kinases 1/2 (MEK-1/2), completely blocked TGF-β1-induced MCP-1 expression. Knockdown of the BAMBI gene promoted phosphorylation of ERK1/2 and TGF-β1-induced expression of MCP-1. Overexpression of BAMBI inhibited phosphorylation of ERK1/2 and TGF-β1-induced upregulation of MCP-1.

Conclusion:

In rat renal tubular epithelial cells, metformin prevents TGF-β1-induced MCP-1 expression, in which BAMBI-mediated inhibition of MEK/ERK1/2 might be involved.

Keywords:

BAMBI MCP-1 TGF-β1 metformin renal tubular epithelial cell

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