Methylation determines fibroblast activation and fibrogenesis in the kidney
By W. Bechtel, Scott McGoohan, E. Zeisberg, Gerhard A. Müller, H. Kalbacher, David Salant, C. Müller, Raghu Kalluri, M. Zeisberg. Nature Medicine, 2010
627 citations recorded by the source corpus.
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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/e19fd1ab14c1730b979517fd154743e6d0e18ff1
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Citations in the corpus
- Kidney fibrosis: from mechanisms to therapeutic medicines (2023, background): “DNA methylation could be inherited by progeny, which could explain the perpetuation of myofibroblast activation.(177) Moreover, hypermethylation of antifibrotic genes like secreted frizzled-related proteins 5 (sFRP5),(178) KLOTHO,(179,180) and Krüppel-like factor 4 (KLF4) also contribute to renal fi”
- Fibroblasts: origins, definitions, and functions in health and disease (2021, background): “Extended exposure to profibrotic signals, such as TGF-b, results in initial suppression and subsequent hypermethylation of the RASAL1 promoter, which causes irreversible transcriptional suppression, lastingmyofibroblast activation, and chronic fibrogenesis (Bechtel et al., 2010).”
- Epithelial to Mesenchymal Transition induces cell cycle arrest and parenchymal damage in renal fibrosis (2015, neutral): “But understanding the complex mechanisms and cellular mediators of kidney fibrosis could offer new therapeutic avenues 3–5 .”
- Integrating mechanisms of pulmonary fibrosis (2011, background): “A recent genome-wide methylation scan of fibroblasts revealed several DNA methylation modifications that were unique to collagen-secreting myofibroblasts obtained from fibrotic kidneys (Bechtel et al., 2010).”
- Mechanisms of fibrosis: therapeutic translation for fibrotic disease (2012, positive): “A recent genome-wide methylation scan of fibroblasts revealed several DNA methylation modifications that were unique to collagen-secreting myofibroblasts obtained from fibrotic mouse kidneys 122 .”
- Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. (2012, background): “In the fibrotic kidney, DNMT1 is associated with persistent fibroblast activation and fibrogenesis via promotion of hypermethylation of RASAL1, a gene that encodes an inhibitor of the Ras oncogene.(35) DNMT1 / heterozygous mice exhibit reduced renal fibrogenesis and kidney fibrosis.”
- Cellular and molecular mechanisms in kidney fibrosis. (2014, positive): “Perhaps the most insightful studies on reprogramming of myofibroblasts have focused on DNA methylation patterns in human cells grown from diseased versus normal kidney (70).”
- The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “A similar perpetuation of the EMT program is accompanied by promoter hypermethylation of a Ras inhibitor during kidney fibrogenesis (Bechtel et al. 2010).”
- Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. (2012, background): “As cell cycle arrest and epigenetic changes appear to be sequential in nature, they may form pathways amenable to interruption.(63,73,75,76)”
- Cellular and molecular mechanisms of renal fibrosis (2011, background): “In addition, the hypoxic and fibrotic microenvironment might lead to perturbed cellular signaling and induce epigenetic modifications, which could contribute to increased fibroblast proliferation, activation and fibrogenesis”