Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats

Li, Guangming; Xie, Qing; Shi, Yi; Li, Ding-Guo; Zhang, Mingjun; Jiang, Shan; Zhou, Huidi; Lu, Huiqing; Jin, Youxin

doi:10.1002/jgm.894

Cited by 151 publications

(119 citation statements)

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“…34 Smad3 signaling has been identified as the responsible pathway inducing CTGF expression in hepatocytes of CCl 4 -treated mice, 35 and knockdown of CTGF by injection of small interfering RNA into the portal veins of rat livers prevents CCl 4 -induced fibrosis by inhibiting TGF-b induction and HSC activation. 36 It has been reported that in rats treated with CCl 4 silymarin decreases CTGF to improve liver fibrosis 37 and curcumin significantly attenuates the severity of liver damage through inhibition of CTGF expression. 30 Our findings confirmed that chronic CCl 4 administration markedly enhanced the intrahepatic expression of CTGF mRNA and protein, and that melatonin significantly reduced these CCl 4 -induced increases.…”

Section: Discussionmentioning

confidence: 99%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl 4 ). Mice in treatment groups received CCl 4 5 mL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl 4 administration. Treatment with CCl 4 resulted in fibrosis evidenced by the staining of Van Gieson and a-smooth muscle actin (a-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl 4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-b, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of a-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-b, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl 4 -induced liver fibrosis. (Translational Research 2015;165:346-357) Abbreviations: a-SMA ¼ a-smooth muscle actin; CCl 4 ¼ carbon tetrachloride; CTGF ¼ connective tissue growth factor; HSC ¼ hepatic stellate cell; MMP-9 ¼ matrix metalloproteinase 9; Nrf2 ¼ nuclear factor erythroid 2-related factor 2; PDGF ¼ platelet-derived growth factor; TGF-b ¼ transforming growth factor b; TIMP-1 ¼ tissue inhibitor of metalloproteinase 1 H epatic fibrosis is a reversible wound-healing response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by an excessive deposition of extracellular matrix (ECM) resulting in liver dysfunction and irreversible cirrhosis. During liver fibrogenesis, hepatic stellate cells (HSCs) undergo activation to a a-smooth muscle actin (SMA)-positive myofibroblastic phenotype and synthesize excess ECM components, particularly collagen. 1 Among the numerous From the

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Section: Discussionmentioning

confidence: 99%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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“…Previous studies have suggested the implications of CTGF in the pathogenesis of hepatic fibrosis characterized by deposition of fibrillar collagens in the liver 21, 44, 45, 46. The full‐length CTGF molecule comprises four structural domains, that is modules 1–4, which are susceptible to proteolysis by hepatic stellate cells, yielding C‐terminal fragments composed of the modules 3 and 4 or the module 4 alone 46.…”

Section: Discussionmentioning

confidence: 99%

MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

George

Tsutsumi

Tsuchishima

2017

J Cellular Molecular Medi

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Connective tissue growth factor (CTGF) is involved in inflammation, pathogenesis and progression of liver fibrosis. Matrix metalloproteinase‐13 (MMP‐13) cleaves CTGF and releases several fragments, which are more potent than the parent molecule to induce fibrosis. The current study was aimed to elucidate the significance of MMP‐13 and CTGF and their downstream effects in liver injury and fibrosis. Hepatic fibrosis was induced using intraperitoneal injections of N‐nitrosodimethylamine (NDMA) in doses of 10 μg/g body weight on three consecutive days of each week over a period of 4 weeks in both wild‐type (WT) and MMP‐13 knockout mice. Administration of NDMA resulted in marked elevation of AST, ALT, TGF‐β1 and hyaluronic acid in the serum and activation of stellate cells, massive necrosis, deposition of collagen fibres and increase in total collagen in the liver of WT mice with a significant decrease in MMP‐13 knockout mice. Protein and mRNA levels of CTGF, TGF‐β1, α‐SMA and type I collagen and the levels of MMP‐2, MMP‐9 and cleaved products of CTGF were markedly increased in NDMA‐treated WT mice compared to the MMP‐13 knockout mice. Blocking of MMP‐13 with CL‐82198 in hepatic stellate cell cultures resulted in marked decrease of the staining intensity of CTGF as well as protein levels of full‐length CTGF and its C‐terminal fragments and active TGF‐β1. The data demonstrate that MMP‐13 and CTGF play a crucial role in modulation of fibrogenic mediators and promote hepatic fibrogenesis. Furthermore, the study suggests that blocking of MMP‐13 and CTGF has potential therapeutic implications to arrest liver fibrosis.

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“…Both cytokines are up-regulated in the skin of SSc patients and strongly stimulate matrix synthesis by dermal fibroblasts. Accordingly, blockade of TGF␤ or PDGF signaling has been shown to reduce the development of fibrosis in various experimental models (6)(7)(8)(9). However, substances that specifically inhibit PDGF pathways are not yet available for clinical application.…”

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confidence: 99%

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

361

273

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Objective. Imatinib mesylate is a clinically welltolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor ␤ (TGF␤) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).Methods. The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycininduced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.Results. Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF␤ and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. Conclusion. These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

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Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats

Abstract: Silencing CTGF expression with siRNA demonstrates therapeutic potential to prevent liver fibrosis by inhibiting HSC activation with consequent extracellular matrix accumulation and the upregulation of TGF-beta1 gene expression.

Cited by 151 publications

References 36 publications

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

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