Methylation determines fibroblast activation and fibrogenesis in the kidney

被引：516

作者：

Bechtel, Wibke ^{[1
,2
]}

McGoohan, Scott ^{[1
,2
]}

Zeisberg, Elisabeth M. ^{[1
,2
]}

Mueller, Gerhard A. ^{[3
]}

Kalbacher, Hubert ^{[4
]}

Salant, David J. ^{[5
]}

Mueller, Claudia A. ^{[4
]}

Kalluri, Raghu ^{[1
,2
]}

Zeisberg, Michael ^{[1
,2
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Boston, MA USA

[3] Univ Gottingen, Med Ctr, Dept Nephrol & Rheumatol, Gottingen, Germany

[4] Univ Med Clin, Sect Transplantat Immunol & Immunohematol, Med Res Ctr, Tubingen, Germany

[5] Boston Univ, Med Ctr, Renal Sect, Boston, MA USA

来源：

NATURE MEDICINE | 2010年 / 16卷 / 05期

基金：

美国国家卫生研究院;

关键词：

TO-MESENCHYMAL TRANSITION; HUMAN RENAL FIBROBLASTS; DNA METHYLATION; INTERSTITIAL FIBROSIS; TGF-BETA; DISEASE; CANCER; PROTEIN; CELLS; IDENTIFICATION;

D O I：

10.1038/nm.2135

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Fibrogenesis is a pathological wound repair process that fails to cease, even when the initial insult has been removed. Fibroblasts are principal mediators of fibrosis, and fibroblasts from fibrotic tissues fail to return to their quiescent stage, including when cultured in vitro. In a search for underlying molecular mechanisms, we hypothesized that this perpetuation of fibrogenesis is caused by epigenetic modifications. We demonstrate here that hypermethylation of RASAL1, encoding an inhibitor of the Ras oncoprotein, is associated with the perpetuation of fibroblast activation and fibrogenesis in the kidney. RASAL1 hypermethylation is mediated by the methyltransferase Dnmt1 in renal fibrogenesis, and kidney fibrosis is ameliorated in Dnmt1(+/-) heterozygous mice. These studies demonstrate that epigenetic modifications may provide a molecular basis for perpetuated fibroblast activation and fibrogenesis in the kidney.

引用

页码：544 / U75

页数：8

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