Effect of TET2 on the pathogenesis of diabetic nephropathy through activation of transforming growth factor β1 expression via DNA demethylation

Aims: Transforming growth factor beta 1 (TGF beta 1) plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). However, the mechanism of its expression and activation induced by high glucose (HG) is still unclear. We mainly explored the role of ten-eleven translocation enzyme-2 (TET2) in regulating TGF beta 1 expression in the process of DN. Main methods: Human mesangial cells (HMCs) and db/db mice were used to analyze the biological effects of hyperglycemia both in vivo and in vitro. Gene expression levels, cell proliferation, protein recruitment levels to TGF beta 1 regulatory region, DNA methylation statues and pathological changes in kidney were tested in different groups. Short hairpin RNA(shRNA) and oral inhibitor were used to knock down or inhibit TET2 expression. Key findings: Our study demonstrated that TET2 expression was increased in the renal cortex of db/db mice and in HMCs inducing by HG. We also found that TET2 binding was increased while DNA methylation of CpG islands was reduced in the TGF beta 1 regulation region in HG, resulting in the increased expression level of TGF beta 1 and cell phenotype transformation. More importantly, clinical research revealed that gradually decreased DNA methylation in the TGF beta 1 regulatory region was also present in patients with diabetes and DN. Significance: Our work suggests that TET2 plays an important role in the pathogenesis of DN by activating TGF beta 1 expression through demethylation of CpG islands in the TGF beta 1 regulatory region. This may provide a potential new therapeutic target for DN.