HDAC6通过靶向调节Smad7赖氨酸脱乙酰化调控TGF-β/Smads信号通路参与糖尿病肾病肾小球硬化

糖尿病肾病时，TGF-β/Smads信号通路的激活可导致系膜细胞大量表达细胞外基质蛋白，这些蛋白分泌到系膜细胞外并沉积在肾小球内，导致肾小球硬化，最终发展为肾脏纤维化。Smad7可负调节TGF-β/Smads信号通路改善肾小球硬化，预实验发现HDAC6在DN小鼠肾脏中表达升高，抑制HDAC6可抑制Smad7的脱乙酰化和TGF-β/Smads信号通路。我们提出HDAC6可通过靶向调节Smad7脱乙酰化并影响其稳定性来调控TGF-β/Smads信号通路，参与糖尿病肾病肾小球硬化的假说。建立高糖与TGF-β诱导的胞外基质蛋白高表达细胞模型，通过抑制/下调或上调系膜细胞中HDAC6的表达，观察抑制或沉默HDAC6是否可以抑制TGF-β/Smads信号通路改善胞外基质堆积，相反，过表达HDAC6能否促进TGF-β/Smads信号通路并加重胞外基质堆积，并在糖尿病肾病动物模型上进一步验证这一假设。

TGF-β/Smads signaling pathway is activated in diabetic nephropathy (DN), and the activation of this pathway leads to excess expression of extracellular matrix proteins in mesangial cells, which are secreted outside the mesangial cells and then deposited in glomeruli, it causes glomerular sclerosis and eventually develops into renal fibrosis. Smad7 can improve glomerular sclerosis via inhibiting TGF-β/Smads signaling pathway. However, the expression of Smad7 is down-regulated in DN. The preliminary experiment found that HDAC6 was elevated in DN kidney, and inhibition of HDAC6 could increase acetylated Smad7 in high glucose-induced mesangial cells and inhibit TGF-β/Smads signaling pathway, it was indicated that HDAC6, Smad7 and TGF-β/Smads signaling pathway could interact with each other in DN. Therefore, we speculate that HDAC6 participates in diabetic nephropathy glomerulosclerosis by targeting Smad7 lysine deacetylation to regulate TGF-β/Smads signaling pathway. Treated the mesangial cells with high glucose or TGF-β1 to establish the diabetic nephropathy cell model, then cotreated with HDAC6 inhibitor, downregulated the expression of HDAC6 by small interfering RNA, upregulated the expression of HDAC6 by transfected the overexpressed HDAC6 plasmid to observe whether inhibition or silencing of HDAC6 can inhibit TGF-β/Smads signaling pathway to improve extracellular matrix accumulation, conversely, whether overexpression of HDAC6 can promote TGF-β/Smads signaling pathway and increase extracellular matrix accumulation, we will further establish diabetic nephropathy animal model to confirm our hypothesis.