MRTF-A介导高糖诱导的肾小管上皮细胞转分化的表观遗传学机制

The epigenetic regulation mediated by MRTF-A has been clarified to associate with pathogenesis of diabetic nephropathy (DN) in animal model. However, whether the effect of MRTF-A is associated with the hyperglycemia-induced EMT of renal tubular epithelial cells and its epigenetic mechanisms remain unclear. To examine this, HK-2 cells and mouse model of DN will be stimulated with medicine, siRNA transfection or gene knockdown. This study will clarify the following assumptions. ① Hyperglycemia stimulates the activation of SRF signaling in HK-2 by activating RhoA/ROCK signal pathway. ② The stimulation of hyperglycemia activates MRTF-A by degradating E-cadherin in Ca2+-dependant and resultant dissociation of actin-MRTF-A complex. ③ The activated SRF/MRTF-A mediates hyperglycemia-induced EMT of HK-2 cells by promoting H3K4 methylate in histone proteins and resultant transcription of target genes. Our study will clarify novel epigenetic mechanisms of DN and contribute to target therapy in ameliorating RIF and treating DN.

心激素相关转录因子-A(MRTF-A)介导的表观遗传学调控机制被证实广泛参与糖尿病肾病(DN)的发病，但其是否通过介导高糖诱导的肾小管上皮细胞-间充质细胞转分化(EMT)发挥作用，其表观遗传学调控机制如何目前尚不清楚。本研究将以肾小管上皮细胞HK-2及糖尿病肾病小鼠模型为研究对象，采用药物干预、siRNA沉默和基因工程等技术干预细胞及模型动物，并进行相关指标的检测，以明确如下创新性研究假设：① 高糖刺激通过激活RhoA/ROCK信号通路活化肾小管上皮细胞SRF信号通路；② 高糖刺激通过促进Ca2+内流降解E-cadherin，解离Actin-MRTF-A复合物以活化MRTF-A；③ 高糖激活的SRF/MRTF-A信号通路通过诱导目的基因启动子序列组蛋白H3K4的甲基化促进纤维化基因转录实现肾小管上皮细胞EMT的表观遗传学调控。本研究将为糖尿病肾病的靶向治疗提供新的理论依据。

心激素相关转录因子-A(MRTF-A)介导的表观遗传学调控机制被证实广泛参与糖尿病肾病(DN)的发病，本研究以肾小管上皮细胞HK-2及糖尿病肾病小鼠模型为研究对象，采用药物干预、siRNA沉默和基因工程等技术干预细胞及模型动物，并进行相关指标的检测，证实表观遗传学通过介导高糖诱导的肾小管上皮细胞-间充质细胞转分化(EMT)发挥作用，具体分子信号机制如下：① 高糖刺激通过激活RhoA/ROCK信号通路活化肾小管上皮细胞SRF信号通路；② 高糖刺激通过促进Ca2+内流降解E-cadherin，解离Actin-MRTF-A复合物以活化MRTF-A；③ 高糖激活的SRF/MRTF-A信号通路通过诱导目的基因启动子序列组蛋白甲基化促进纤维化基因转录实现肾小管上皮细胞EMT的表观遗传学调控。本研究为糖尿病肾病的靶向治疗提供一定地理论基础。