Methylation and Kidney Fibrosis

A team of scientists led by Drs. Kalluri and Zeisberg of Harvard suggested that demethylation reduced kidney fibrosis in mice.

The potential mechanisms of this effect may be various.  They found that a RAS inhibitor, RASAL1, is hypermethylated in renal fibrosis.

Nat Med. 2010 May;16(5):544-50. Epub 2010 Apr 25.
Methylation determines fibroblast activation and fibrogenesis in the kidney.
Bechtel W, McGoohan S, Zeisberg EM, Müller GA, Kalbacher H, Salant DJ, Müller CA, Kalluri R, Zeisberg M.
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Comment in:
Nat Med. 2010 May;16(5):523-5.
Kidney Int. 2010 Sep;78(5):430.
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.
PMID: 20418885 [PubMed - indexed for MEDLINE]

Fstl1 is a BMP4 signaling antagonist in controlling mouse lung development

	Proc Natl Acad Sci U S A. 2011 Apr 11. [Epub ahead of print] Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Geng Y, Dong Y, Yu M, Zhang L, Yan X, Sun J, Qiao L, Geng H, Nakajima M, Furuichi T, Ikegawa S, Gao X, Chen YG, Jiang D, Ning W. Model Animal Research Center, Nanjing University, Nanjing 210061, China. Abstract Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-β/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling. PMID: 21482757 [PubMed - as supplied by publisher]
	PMID: 21482757 [PubMed - as supplied by publisher]

G2/M unrest and kidney fibrosis

Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV.

Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Comment in:

Nat Med. 2010 May;16(5):523-5.
Abstract
Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major

contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.

http://www.ncbi.nlm.nih.gov/pubmed/20436483
[PubMed - indexed for MEDLINE]

pirfenidone approved for idiopathic pulmonary fibrosis in EU

Nat Biotechnol. 2011 Apr;29(4):301.

p38 kinase inhibitor approved for idiopathic pulmonary fibrosis.

Moran N.

PMID: 21478838 [PubMed - in process]

{beta}-Arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix.

Sci Transl Med. 2011 Mar 16;3(74):74ra23.
{beta}-Arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix.
Lovgren AK, Kovacs JJ, Xie T, Potts EN, Li Y, Foster WM, Liang J, Meltzer EB, Jiang D, Lefkowitz RJ, Noble PW.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Abstract
Idiopathic pulmonary fibrosis is a progressive disease that causes unremitting extracellular matrix deposition with resulting distortion of pulmonary architecture and impaired gas exchange. β-Arrestins regulate G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors through receptor desensitization while also acting as signaling scaffolds to facilitate numerous effector pathways. Here, we examine the role of β-arrestin1 and β-arrestin2 in the pathobiology of pulmonary fibrosis. In the bleomycin-induced mouse lung fibrosis model, loss of either β-arrestin1 or β-arrestin2 resulted in protection from mortality, inhibition of matrix deposition, and protected lung function. Fibrosis was prevented despite preserved recruitment of inflammatory cells and fibroblast chemotaxis. However, isolated lung fibroblasts from bleomycin-treated β-arrestin-null mice failed to invade extracellular matrix and displayed altered expression of genes involved in matrix production and degradation. Furthermore, knockdown of β-arrestin2 in fibroblasts from patients with idiopathic pulmonary fibrosis attenuated the invasive phenotype. These data implicate β-arrestins as mediators of fibroblast invasion and the development of pulmonary fibrosis, and as a potential target for therapeutic intervention in patients with idiopathic pulmonary fibrosis.

PMID: 21411739 [PubMed - in process]