Renal fibrosis is the hallmark of chronic kidney disease, a prominent problem in clinical nephrology. Unlike physiologic repair of acute kidney injury, progressive renal fibrosis is a self-contained perpetuated process, which fails to cease even when the initial insult has been eliminated. Activated fibroblasts are the main mediators of fibrosis, and fibroblasts isolated from fibrotic kidneys even fail to return to their quiescent state when cultured in vitro. The molecular mechanisms that underlie this persisting fibroblast activation are not yet known. In a genomewide methylation screen we identified the Ras inhibitor RASAL1 as one of 13 genes to be methylated in fibroblasts from fibrotic kidneys, but not in fibroblasts from non-fibrotic kidneys. The central hypothesis of this grant application is that 'hypermethylation of RASAL1, a suppressor of the Ras proto-oncogene, in renal fibroblasts prevents them from returning to their quiescent state and perpetuates progression of fibrogenesis"""""""". Based on the preliminary data we will elucidate if hypermethylation of RASAL1 causes perpetuated fibroblast activation via Ras hyperactivity, ultimately leading to renal fibrosis.

Public Health Relevance

Renal fibrosis is a major problem in clinical Nephrology, because it causes progressive loss of kidney function, requiring dialysis or kidney transplantation to circumvent instant fatality. Specific therapies to halt - or even reverse - are not yet available in the clinic, making further understanding of the underlying pathomechanisms relevant. Fibrosis resembles wound repair. However, unlike wound repair, fibrogenesis does not cease once the initial insult has been contained, causing perpetuated scar tissue formation which results in kidney failure. The reason why the fibrotic process fails to stop in some patients is not known. This application will elucidate the role of epigenetic changes, which are relatively stable modifications of DNA, in renal fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Hoshizaki, Deborah K
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Beth Israel Deaconess Medical Center
United States
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