Role of DNA De Novo (De)Methylation in the Kidney in Salt-Induced Hypertension.
Role of DNA De Novo (De)Methylation in the Kidney in Salt-Induced Hypertension.
复制标题
DOI：
10.1161/hypertensionaha.118.11650
复制
发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Liang M
中科院分区：
文献类型：
--
作者：
Liu P;Liu Y;Liu H;Pan X;Li Y;Usa K;Mishra MK;Nie J;Liang M
许多涉及主要由非分裂细胞组成的组织的成人疾病与DNA甲基化的变化有关。提示DNA甲基转移酶3（Dnmt 3）和10 - 11易位酶（泰特）催化的DNA从头甲基化或去甲基化具有病理生理作用。然而，DNA从头甲基化（去甲基化）对这些疾病的贡献仍然几乎完全未经证实。在Dahl SS大鼠的肾脏外髓质中，DNA甲基化在几天内发生了广泛的变化，Dahl SS大鼠被喂食高盐饮食，这是一种典型的高血压模型。肾内施用抗Dnmt 3a/Tet 3 GapmeR减轻SS大鼠中的高盐诱导的高血压。高盐饮食诱导了1,712个基因在肾脏外髓质的差异表达。值得注意的是，这些基因中76%的差异表达被抗Dnmt 3a/Tet 3 GapmeR阻止。响应于GapmeR的差异表达的基因参与代谢和炎症的调节，并且显著富集响应于GapmeR的显示差异甲基化的基因。这些数据表明SS大鼠肾脏中DNA从头甲基化（去甲基化）在高血压的发展中具有重要作用。这些发现应该有助于将涉及非分裂细胞疾病的DNA甲基化研究范式从相关分析转向功能和机制研究。
Numerous adult diseases involving tissues consisting primarily of non-dividing cells are associated with changes in DNA methylation. It suggests a pathophysiological role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 (Dnmt3) and ten-eleven translocases (Tet). However, the contribution of DNA de novo (de)methylation to these diseases remains almost completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intra-renal administration of anti-Dnmt3a/Tet3 GapmeR’s attenuated high salt-induced hypertension in SS rats. The high salt diet induced differential expression of 1,712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes were prevented by anti-Dnmt3a/Tet3 GapmeR’s. The genes differentially expressed in response to the GapmeR’s were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeR’s. These data indicate a significant role of DNA de novo (de)methylation in the kidney in the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving non-dividing cells from correlative analysis to functional and mechanistic studies.