title: Methylation determines fibroblast activation and fibrogenesis in the kidney.
abstract: 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.
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wibke
authors.initials: W
authors.lastname: Bechtel
authors.forename: Scott
authors.initials: S
authors.lastname: McGoohan
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Zeisberg
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Müller
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: David J
authors.initials: DJ
authors.lastname: Salant
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Müller
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
mesh_terms: D000818:Animals; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D015689:Oncogene Protein p21(ras)