Journal
NATURE MEDICINE
Volume 16, Issue 5, Pages 544-U75Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2135
Keywords
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Funding
- National Institutes of Health [R01DK081576, R03DK081687, R01DK30932, R01DK55001, R01CA125550, 1K08 CA129204, K08 DK074558]
- American Society of Nephrology
- American Heart Association [SDG0735602T]
- Deutsche Forschungsgemeinschaft-Stipendium [BE4211/1-1]
- Champalimaud Metastasis Research Program
- Beth Israel Deaconess Medical Center for the Division of Matrix Biology
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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.
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