Epigenetic activation of CTGF transcription by high glucose in renal tubular epithelial cells is mediated by myocardin-related transcription factor A

Diabetic nephropathy (DN) is one of the most devastating complications of diabetes. Connective tissue growth factor (CTGF) levels are up-regulated in patients with DN and in renal tubular epithelial cells (RTECs) exposed to high glucose (HG). The underlying epigenetic mechanism remains to be elucidated. In the present study, we investigate the role of myocardin-related transcription factor A (MRTF-A) in HG-induced CTGF transcription in RTECs. We report that in two different animal models of DN, one induced by streptozotocin (STZ) injection and the other induced by high-fat diet (HFD) feeding, MRTF-A deficiency attenuated CTGF induction in the kidneys. In cultured RTECs, MRTF-A knockdown similarly ameliorated CTGF induction by HG treatment. Upon CTGF induction, there was an increase in acetylated histone H3 (AcH3) and trimethylated H3K4 (H3K4Me3) on the CTGF promoter region accompanying a decrease in dimethylated H3K9 (H3K9Me2). MRTF-A ablation in vivo or depletion in vitro comparably dampened the accumulation of AcH3 and H3K4Me3 but restored H3K9Me2 on the CTGF promoter. Further analyses revealed that MRTF-A interacted with and recruited histone demethylase KDM3A to the CTGF promoter to activate transcription. KDM3A silencing equivalently weakened HG-induced CTGF induction in RTECs. In conclusion, MRTF-A contributes to HG-induced CTGF transcription via an epigenetic mechanism.