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]

Hinz and Gabbiani: Fibrosis: recent advances in myofibroblast

From F1000 Biology Reports

Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives

Boris Hinz¹ and Giulio Gabbiani²

1. Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON M5S 3E2, Canada
2. Department of Pathology and Immunology, CMU, University of Geneva, Rue Michel-Servet 1, 1211, Switzerland

Corresponding author

F1000 Biol Reports2010, 2:78 (doi: 10.3410/B2-78)

Published: 11 Nov 2010

© 2010 Faculty of 1000 Ltd

The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/2/78

Abstract

The crucial role of the myofibroblast in wound healing and fibrosis development is well established. This review discusses the mechanisms of myofibroblast action and the new findings that may develop into therapeutic strategies during the next few years.

Introduction and context

Tissue destruction by organ fibrosis contributes to the lethal outcomes associated with heart, lung, liver, kidney, and skin diseases. The cell responsible for the detrimental fibrotic tissue contractures is the myofibroblast, which has a phenotype characterized by excessive production of collagenous extracellular matrix (ECM) and tensile force [1]. The concept that the myofibroblast plays a pivotal role in the establishment of fibrotic conditions has paved the way for a new approach in the understanding of the mechanisms of these pathologic situations [2]. In particular, it has become accepted that mechanical force generation by myofibroblasts, which in turn depends on the neo-expression of α-smooth muscle actin (α-SMA) in stress fibers of these cells, regulates essential phenomena for tissue remodeling, such as cytokine synthesis and ECM component production [2]. The myofibroblast participates in a variety of phenomena, including embryologic development, organ fibrosis, and the stroma reaction to epithelial tumors [1]. This widespread occurrence suggests that the term myofibroblast describes a functional status rather than a fixed cell type. This assumption has been supported by recent findings indicating that myofibroblasts originate from a spectrum of cellular sources depending on the physiological or pathological situation [1]. Myofibroblast origin and its tissue environment should be considered when planning new therapeutic strategies that aim at decreasing myofibroblast number or activity.

Major recent advances

The list of cells from which myofibroblasts can derive has grown impressively during the last years. It includes local fibroblasts, epithelial cells, endothelial cells, smooth muscle cells, pericytes, hepatic perisinusoidal cells, mesenchymal stem cells, and bone marrow-derived cells known as fibrocytes [1,3]. Most attention has been given to the fibrocyte as a possible myofibroblast precursor [4] and the phenomena of epithelial- and endothelial-mesenchymal transition as myofibroblast sources, particularly during lung and kidney fibrosis [5,6]. Transition of epithelial cells all the way to the myofibroblast phenotype is inducible in culture and regulated by different signaling pathways [7,8]. However, the relative contribution of myofibroblast precursors remains to be determined. As one would intuitively expect, it appears likely that in most situations local fibroblasts represent the major source of myofibroblasts [1]. The local derivation of myofibroblasts from mesenchymal rather than epithelial or endothelial cells has recently been documented in a model of renal interstitial fibrosis by means of genetic lineage tracing [9].

At present there is no accepted therapy for fibrotic diseases [10]. A number of previous and recent antifibrotic strategies attempt to interfere with myofibroblast formation by targeting key factors in the differentiation process (Figure 1). It is well established that myofibroblast differentiation and organ fibrosis are predominantly controlled by transforming growth factor β1 (TGF-β1) [11] and the ED-A (extra domain A) found in cellular fibronectin [12]. Moreover, several cytokines and chemokines (and their receptors), as well as coagulation factors and ECM components, have been implicated in this process [13-18]. It is likely that the heterogeneity of the myofibroblast origin requires specific factors and specific mechanical conditions in each situation.

Figure 1. Targeting the myofibroblast Potential antifibrotic therapies can interfere with the chemical and mechanical factors that lead to myofibroblast formation from different precursor cells (shown here for fibroblasts). Alternatively, or additionally, specific features of the differentiated myofibroblast can be targeted to induce myofibroblast regression and/or apoptosis. α-SMA, alpha-smooth muscle actin; ECM, extracellular matrix; ED-A, extra domain A; IST-9; fibronectin antibody; TGFβ1, transforming growth factor β1. 

Fibrosis is usually diagnosed when tissue destruction is already progressing, and it is possible that therapies will have to target the resident myofibroblast population. For this, aiming at the contractile apparatus is allegedly the most straight forward and promising strategy to inhibit myofibroblast function (Figure 1). A new direction, which has proven experimentally successful, is based on the observation that intracellular delivery of the α-SMA amino-terminal sequence Ac-EEED inhibits the incorporation of this protein in myofibroblast stress fibers, thus reducing force production as well as collagen type I synthesis by myofibroblasts in vitro; moreover, it significantly inhibits experimental wound contraction in vivo [19]. Due to its relative specificity for α-SMA-expressing myofibroblast stress fibers, this peptide appears as a good candidate for topical (e.g., burn scars) and systemic (e.g., organ fibrosis) administration.

Another promising strategy to induce myofibroblast disappearance is to stimulate them to go into apoptosis. Two major intracellular pathways have been identified that act pro-survival (or anti-apoptotic) for the myofibroblast: focal adhesion kinase signaling in cell ECM adhesions and phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Focal adhesion kinase activation protects myofibroblasts from going into apoptosis in response to the loss of cell adhesion, a phenomenon called anoikis [20]. TGF-β1 and endothelin-1 have been shown to independently activate the PI3K-AKT pathway and thereby render myofibroblasts apoptosis-resistant [21]. Development of protein kinase inhibitors as specific inducers of myofibroblast apoptosis is an exciting new avenue in fighting fibrosis [22]. Other strategies could include myofibroblast-specific delivery of apoptosis-inducing drugs as applied in a mouse model of liver fibrosis [23].

Inducing myofibroblast disappearance does not necessarily include their killing; interrupting the auto/paracrine production of active TGF-β1 leads to myofibroblast de-differentiation, at least in vitro [24]. However, attempts to use general inhibitors of TGF-β1 have been relatively unsuccessful, showing that fibrosis development is a more complex phenomenon than expected [25-28]. The limitation of such global strategies is the interference of the beneficial effects of the pleiotrophic TGF-β1, such as controlling homeostasis of epithelial, vascular, endothelial, and immune cells. Therefore, more promising strategies may be to prevent latent TGF-β1 activation in a cell-type-specific manner rather than blocking already active TGF-β1. TGF-β1 is secreted together with LAP (latency-associated peptide), forming a large complex with latent TGF-β1 binding protein 1 (LTBP-1) in the ECM [29]. Epithelial cells activate latent TGF-β1 via integrin αvβ6 [30,31], which requires ECM binding mediated by LTBP-1 [29]. Inhibition of the epithelium-specific αvβ6 integrin protects from lung, kidney, and bile duct fibrosis [32-35]. In addition, integrins αvβ3, αvβ8, and αvβ5 play a role in latent TGF-β1 activation by fibroblastic cells, either directly or in a process involving proteases [11,36-40]. We have described a novel mechanical mechanism of latent TGF-β1 activation for myofibroblasts that, literally, pulls on the large latent complex using the integrin αvβ5 [41].

Future directions

Blocking specific integrins is a promising future strategy to control the development of myofibroblasts in fibrotic disorders (Figure 1). In addition to blocking the latent TGF-β1-activating integrin αvβ5 [41-44], inhibition of integrin α3 [8,45], α11, [46] αvβ3 [44,47], and β1 [48] were shown to block myofibroblast development and may be developed into future therapies. The latter integrins are all implicated in myofibroblast mechanoperception and transduction. It becomes increasingly clear that myofibroblast differentiation crucially depends on mechanical factors such as ECM stiffness and intracellular tension. Mechanical stress determines the stress fiber localization of α-SMA [49], modulates α-SMA promoter activity and protein expression in a process that involves the myocardin-related transcription factor [7,48,50], and modulates the bioactivity of TGF-β1 [41]. Hence, releasing myofibroblasts from stress – for example, using the Ac-EEED peptide [51] – will have a profound and long-term effect on myofibroblast persistence and may even induce myofibroblast apoptosis [52].

Abbreviations

α-SMA, alpha-smooth muscle actin; ECM, extracellular matrix; PI3K, phosphatidylinositol 3-kinase; LTBP-1, latent transforming growth factor β1 binding protein 1; TGF-β1, transforming growth factor β1.

Competing Interests

The authors declare that they have no competing interests.

Acknowledgements

The work of BH is supported by grants from the Swiss National Science Foundation (grant# 3100A0-113733/1), the Heart and Stroke Foundation Ontario (grant# NA7086), and the Canadian Institutes of Health Research (grant# 210820).

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Scar-reducing peptide

A recent study by Dr. Erkki Ruoslahti published in PNAS,  using a wound-homing peptide, CARSKNKDC, to tag decorin, in vivo, showed that the peptide-tagged decorin significantly reduced scar formation in mice.

Proc Natl Acad Sci U S A. 2010 Nov 24. [Epub ahead of print]
Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice.
Järvinen TA, Ruoslahti E.

Vascular Mapping Laboratory, Center for Nanomedicine, Sanford-Burnham Medical Research Institute, University of California, Santa Barbara, CA 93106 and Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
Abstract
Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.

PMID: 21106754 [PubMed - as supplied by publisher]