Li Xiangjun, Li Chaoyuan, Li Xiaoxia, Cui Peihe, Li Qifeng, Guo Qiaoyan, Han Hongbo, Liu Shujun, Sun Guangdong
Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin 130021, China.
Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
J Diabetes Res. 2016;2016:3853242. doi: 10.1155/2016/3853242. Epub 2016 Aug 29.
Diabetic nephropathy (DN), a common complication associated with type 1 and type 2 diabetes mellitus (DM), characterized by glomerular mesangial expansion, inflammation, accumulation of extracellular matrix (ECM) protein, and hypertrophy, is the major cause of end-stage renal disease (ESRD). Increasing evidence suggested that p21-dependent glomerular and mesangial cell (MC) hypertrophy play key roles in the pathogenesis of DN. Recently, posttranscriptional modifications (PTMs) have uncovered novel molecular mechanisms involved in DN. However, precise regulatory mechanism of histone lysine methylation (HKme) mediating p21 related hypertrophy associated with DN is not clear. We evaluated the roles of HKme and histone methyltransferase (HMT) SET7/9 in p21 gene expression in glomeruli of diabetic rats and in high glucose- (HG-) treated rat mesangial cells (RMCs). p21 gene expression was upregulated in diabetic rats glomeruli; chromatin immunoprecipitation (ChIP) assays showed decreased histone H3-lysine9-dimethylation (H3K9me2) accompanied with enhanced histone H3-lysine4-methylation (H3K4me1/3) and SET7/9 occupancies at the p21 promoter. HG-treated RMCs exhibited increased p21 mRNA, H3K4me level, SET7/9 recruitment, and inverse H3K9me, which were reversed by TGF-β1 antibody. These data uncovered key roles of H3Kme and SET7/9 responsible for p21 gene expression in vivo and in vitro under diabetic conditions and confirmed preventive effect of TGF-β1 antibody on DN.
糖尿病肾病（DN）是1型和2型糖尿病（DM）常见的并发症，其特征为肾小球系膜扩张、炎症、细胞外基质（ECM）蛋白积聚和肥大，是终末期肾病（ESRD）的主要原因。越来越多的证据表明，p21依赖的肾小球和系膜细胞（MC）肥大在DN的发病机制中起关键作用。最近，转录后修饰（PTM）揭示了参与DN的新分子机制。然而，组蛋白赖氨酸甲基化（HKme）介导与DN相关的p21相关肥大的确切调控机制尚不清楚。我们评估了HKme和组蛋白甲基转移酶（HMT）SET7/9在糖尿病大鼠肾小球和高糖（HG）处理的大鼠系膜细胞（RMC）中p21基因表达中的作用。糖尿病大鼠肾小球中p21基因表达上调；染色质免疫沉淀（ChIP）分析显示组蛋白H3-赖氨酸9-二甲基化（H3K9me2）减少，同时组蛋白H3-赖氨酸4-甲基化（H3K4me1/3）和SET7/9在p21启动子处的占有率增加。HG处理的RMC表现出p21 mRNA、H3K4me水平、SET7/9募集增加以及H3K9me相反变化，这些变化被TGF-β1抗体逆转。这些数据揭示了H3Kme和SET7/9在糖尿病条件下体内和体外对p21基因表达的关键作用，并证实了TGF-β1抗体对DN的预防作用。
