Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease.
Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease.
复制标题
DOI：
10.1016/j.ebiom.2014.11.005
复制
发表时间：
2015-01
期刊：
影响因子：
11.1
通讯作者：
Zeisberg, Michael
中科院分区：
文献类型：
--
作者：
Tampe, Bjoern;Tampe, Desiree;Zeisberg, Elisabeth M.;Mueller, Gerhard A.;Bechtel-Walz, Wibke;Koziolek, Michael;Kalluri, Raghu;Zeisberg, Michael
慢性肾脏疾病的进展仍然是临床肾脏病的主要问题，迫切需要新的治疗方法和生物标志物。异常的启动子CpG岛甲基化和随后的特定基因的转录沉默已经成为慢性肾脏疾病进展的因素。在这里，我们报告了RAS-GTP抑制基因RASAL1的转录沉默是导致肾脏纤维化进展的原因，我们发现外周血中循环中甲基化的RASAL1启动子DNA片段与肾活检组织中RASAL1启动子甲基化水平和纤维化程度相对应，从而能够对肾内CpG岛甲基化进行无创性的纵向分析。通过对高血压性肾病患者的回顾性分析，发现高血压性肾硬化症患者外周血循环中RASAL1基因启动子甲基化片段减少，证明小剂量双氢呋喃延缓了排泄性肾功能的下降，而标准剂量的双氢呋喃则无保护作用。我们证明，双肼肼的保护作用是通过诱导内源性Tet3/TdG介导的DNA去甲基化活性逆转异常的启动子CpG岛甲基化，而标准剂量的HIF1α的诱导抵消了其保护活性。我们认为RASAL1启动子甲基化是肾纤维化的治疗靶点和生物标志物。我们的研究表明，小剂量双氢呋喃在慢性肾脏疾病和纤维化患者中的治疗作用值得进一步考虑。RASAL1启动子异常甲基化是导致肾纤维化进展的原因之一。肾内RASAL1甲基化程度由循环中的RASAL1启动子片段甲基化水平来反映。小剂量肼导致内源性Tet3依赖的去甲基化，抑制肾纤维化的进展。
Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation. Retrospective analysis of patients with hypertensive nephrosclerosis revealed that circulating methylated RASAL1 promoter DNA fragments in peripheral blood decrease with Dihydralazine treatment in patients with hypertensive nephrosclerosis, and provided evidence that low-dose Dihydralazine delays decline of excretory kidney function, whereas Dihydralazine at standard doses had no protective effect. We demonstrate that the protective effect of Dihydralazine is due to induction of endogenous Tet3/Tdg-mediated DNA-de-methylation activity reversing aberrant promoter CpG island methylation, while HIF1α induction at standard doses counterbalances its protective activity. We conclude that RASAL1 promoter methylation is a therapeutic target and a biomarker of renal fibrosis. Our study suggests that therapeutic use of low-dose Dihydralazine in patients with chronic kidney disease and fibrosis deserves further consideration. Aberrant RASAL1 promoter methylation contributes causally to progression of kidney fibrosis. Degree of intrarenal RASAL1 methylation is reflected by levels of circulating methylated RASAL1 promoter fragments. Low-dose Hydralazine induces endogenous Tet3-dependent de-methylation and inhibits progression of kidney fibrosis.
登录
查看更多内容
影响因子：
64.5
作者：
Bhutani N;Burns DM;Blau HM
通讯作者：
Blau HM
影响因子：
3.4
作者：
Coronel, Jaime;Cetina, Lucely;Duenas-Gonzalez, Alfonso
通讯作者：
Duenas-Gonzalez, Alfonso
影响因子：
19.6
作者：
Manucha, W;Oliveros, L;Vallés, P
通讯作者：
Vallés, P
DOI：
10.1126/science.1170116
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tahiliani M;Koh KP;Shen Y;Pastor WA;Bandukwala H;Brudno Y;Agarwal S;Iyer LM;Liu DR;Aravind L;Rao A
通讯作者：
Rao A
影响因子：
5.8
作者：
Chavez-Blanco A;Perez-Plasencia C;Perez-Cardenas E;Carrasco-Legleu C;Rangel-Lopez E;Segura-Pacheco B;Taja-Chayeb L;Trejo-Becerril C;Gonzalez-Fierro A;Candelaria M;Cabrera G;Duenas-Gonzalez A
通讯作者：
Duenas-Gonzalez A