Smooth Muscle α-Actin Deficiency in Myofibroblasts Leads to Enhanced Renal Tissue Fibrosis

Takeji, Masanobu; Moriyama, Toshiki; Oseto, Susumu; Kawada, Noritaka; Hori, Masatsugu; Imai, Enyu; Miwa, Takeshi

doi:10.1074/jbc.m602182200

Cited by 63 publications

(59 citation statements)

References 45 publications

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“…47 Myosin IIB null mutation did not affect the generation of traction force but caused the defect in directional movement resulting in the impairment of cell migration. 48 It has been well established that cytoskeleton molecules such as ␣-SMA and myosin primarily regulate cell migration and traction force generation.…”

Section: Discussionmentioning

confidence: 95%

Small Cytoskeleton-Associated Molecule, Fibroblast Growth Factor Receptor 1 Oncogene Partner 2/Wound Inducible Transcript-3.0 (FGFR1OP2/wit3.0), Facilitates Fibroblast-Driven Wound Closure

Lin

Hokugo

Choi

et al. 2010

The American Journal of Pathology

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Wounds created in the oral cavity heal rapidly and leave minimal scarring. We have examined a role of a previously isolated cDNA from oral wounds encoding wound inducible transcript-3.0 (wit3.0) , also known as fibroblast growth factor receptor 1 oncogene partner 2 (FGFR1OP2). FGFR1OP2/wit3.0 was highly expressed in oral wound fibroblasts without noticeable up-regulation of ␣-smooth muscle actin. In silico analyses , denaturing and nondenaturing gel Western blot , and immunocytology together demonstrated that FGFR1OP2/wit3.0 were able to dimerize and oligomerize through coiled-coil structures and appeared to associate with cytoskeleton networks in oral wound fibroblasts. Overexpression of FGFR1OP2/ wit3.0 increased the floating collagen gel contraction of naïve oral fibroblasts to the level of oral wound fibroblasts , which was in turn attenuated by smallinterfering RNA knockdown. The FGFR1OP2/wit3.0 synthesis did not affect the expression of collagen I as well as procontractile peptides such as ␣-smooth muscle actin , and transforming growth factor-␤1 had no effect on FGFR1OP2/wit3.0 expression. Fibroblastic cells derived from embryonic stem cells carrying FGFR1OP2/wit3.0 (؉/؊) mutation showed significant retardation in cell migration. Thus , we postulate that FGFR1OP2/wit3.0 may regulate cell motility and stimulate wound closure. FGFR1OP2/wit3.0 was not upregulated during skin wound healing; however , when treated with FGFR1OP2/wit3.0 -expression vector, the skin wound closure was significantly accelerated, resulting in the limited granulation tissue formation. Our data suggest that FGFR1OP2/wit3.0 may possess a therapeutic potential for wound management. (Am J

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Section: Discussionmentioning

confidence: 95%

Small Cytoskeleton-Associated Molecule, Fibroblast Growth Factor Receptor 1 Oncogene Partner 2/Wound Inducible Transcript-3.0 (FGFR1OP2/wit3.0), Facilitates Fibroblast-Driven Wound Closure

Lin

Hokugo

Choi

et al. 2010

The American Journal of Pathology

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“…The finding that epimorphin colocalized well with a-SMA-positive cells is somewhat in accordance with this concept because recent reports indicate important roles of a-SMA in the repair of renal fibrosis. 35,36 Syntaxins are the target membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNARE) that mediate intracellular vesicle targeting and fusion. 6,37,38 Among syntaxin members, epimorphin (syntaxin-2) is the only one reported to exert an effect extracellularly as an epithelial morphogen.…”

Section: Discussionmentioning

confidence: 99%

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Yamada¹,

Oda²,

Higashi³

et al. 2010

Laboratory Investigation

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Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelialmesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with antiepimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-b and collagen-I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production.

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“…Moreover, strategies to antagonize contractile proteins also may have unintended consequences. For example, mice lacking α smooth muscle actin protein in myofibroblasts have increased renal fibrosis in experimental glomerulonephritis, 162 suggesting that α-actin induction may be a counter-regulatory response to enhanced fibrogenesis. Moreover, missense mutations of this protein have been linked to aortic aneurysms in human beings, 163 indicating that the protein also may contribute to vascular integrity.…”

Section: Perpetuating Pathwaysmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Smooth Muscle α-Actin Deficiency in Myofibroblasts Leads to Enhanced Renal Tissue Fibrosis

Cited by 63 publications

References 45 publications

Small Cytoskeleton-Associated Molecule, Fibroblast Growth Factor Receptor 1 Oncogene Partner 2/Wound Inducible Transcript-3.0 (FGFR1OP2/wit3.0), Facilitates Fibroblast-Driven Wound Closure

Small Cytoskeleton-Associated Molecule, Fibroblast Growth Factor Receptor 1 Oncogene Partner 2/Wound Inducible Transcript-3.0 (FGFR1OP2/wit3.0), Facilitates Fibroblast-Driven Wound Closure

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Mechanisms of Hepatic Fibrogenesis

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