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.
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.
|LeBleu, Valerie S; O'Connell, Joyce T; Gonzalez Herrera, Karina N et al. (2014) PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16:992-1003, 1-15|
|Melo, Sonia A; Sugimoto, Hikaru; O'Connell, Joyce T et al. (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707-21|
|Charytan, David M; Padera, Robert; Helfand, Alexander M et al. (2014) Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease. Int J Cardiol 176:99-109|
|Özdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L et al. (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719-34|
|Carstens, Julienne L; Lovisa, Sara; Kalluri, Raghu (2014) Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch. J Clin Invest 124:1458-60|
|Tampe, Björn; Tampe, Desiree; Müller, Claudia A et al. (2014) Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol 25:905-12|
|Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie et al. (2014) Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. Am J Pathol 184:2687-98|
|Kahlert, Christoph; Melo, Sonia A; Protopopov, Alexei et al. (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869-75|
|Zeisberg, Michael; Kalluri, Raghu (2013) The Kielin/chordin-like protein checkpoint constitutes a system of checks and balances in CKD. J Am Soc Nephrol 24:863-5|
|Zeisberg, Michael; Kalluri, Raghu (2013) Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol 304:C216-25|
Showing the most recent 10 out of 18 publications