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PMID: 20418885 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Methylation determines fibroblast activation and fibrogenesis in the kidney.

Nature medicine ·Vol. 16 ·No. 5 ·2010-05-00 ·Pages 544-50

Bechtel W, McGoohan S, Zeisberg EM, Müller GA, Kalbacher H, Salant DJ, Müller CA, Kalluri R, Zeisberg M

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.

MeSH Terms
Animals DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases/metabolism DNA Methylation Fibroblasts/metabolism Fibrosis Kidney/metabolism,pathology Mice Mice, Inbred C57BL Mice, Inbred Strains Oncogene Protein p21(ras)/antagonists & inhibitors
Chemicals
DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases Dnmt1 protein, mouse Oncogene Protein p21(ras)
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Bechtel Wibke
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
McGoohan Scott
Zeisberg Elisabeth M
Müller Gerhard A
Kalbacher Hubert
Salant David J
Müller Claudia A
Kalluri Raghu
Zeisberg Michael
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2135
Published
2010-05-00
Epub
2010-00-25
Pages
544-50
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC3106179
Subset
IM
Grants
NIDDK NIH HHS · R01 DK081576-01A2 · United States
NIDDK NIH HHS · R01 DK030932 · United States
NCI NIH HHS · 1K08 CA129204 · United States
NIDDK NIH HHS · R01 DK081576 · United States
NCI NIH HHS · K08 CA129204-03 · United States
NCI NIH HHS · R01CA125550 · United States
NIDDK NIH HHS · R03 DK081687 · United States
NIDDK NIH HHS · R03 DK081687-02 · United States
NCI NIH HHS · R01 CA125550 · United States
NIDDK NIH HHS · R01 DK055001 · United States
NIDDK NIH HHS · R03DK081687 · United States
NIDDK NIH HHS · R01DK55001 · United States
NCI NIH HHS · K08 CA129204 · United States
NIDDK NIH HHS · K08 DK074558-05 · United States
NIDDK NIH HHS · K08 DK074558 · United States
NIDDK NIH HHS · R01DK081576 · United States
NIDDK NIH HHS · R01DK30932 · United States
Corrections
CommentIn
PMID: 20448575
CommentIn
PMID: 20734473
External Links
PubMed source DOI: 10.1038/nm.2135 PMC Full Text View journal details
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