Reduced Liver Fibrosis in Hypoxia-inducible Factor1α-Deficient Mice

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 4063 KLSIC, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 02/2009; 296(3):G582-92. DOI: 10.1152/ajpgi.90368.2008
Source: PubMed


Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. In the present study, the hypothesis was tested that hypoxia-inducible factor-1alpha (HIF-1alpha) is activated in the liver during chronic injury and regulates expression of profibrotic proteins. To investigate this hypothesis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1alpha protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1alpha is required for the development of fibrosis, control and HIF-1alpha-deficient mice were subjected to BDL. Levels of type I collagen and alpha-smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1alpha-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1alpha promotes liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in control mice subjected to BDL compared with HIF-1alpha-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1alpha is a critical regulator of profibrotic mediator production during the development of liver fibrosis.

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Available from: Jeon-Ok Moon, Mar 31, 2014
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    • "HIF-1α expression can activate hepatic stellate cells (HSCs) and fibroblasts to differentiate into myofibroblasts that proliferate and migrate to injured areas where they secrete ECM [64] [65] [66] [67]. In vivo studies using bile duct ligated mice; an animal model of liver fibrosis show increased Hif-1α expression 3 days after surgery, whereas Hif-1α deficient ligated mice show a significant reduction in fibrogenic mediators [66]. "
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    ABSTRACT: Hypoxia inducible transcription factors (HIFs) activate diverse pathways that regulate cellular metabolism, angiogenesis, proliferation and migration, enabling a cell to respond to a low oxygen or hypoxic environment. HIFs are regulated by oxygen-dependent and independent signals including: mitochondrial dysfunction, reactive oxygen species, endoplasmic reticular stress and viral infection. HIFs have been reported to play a role in the pathogenesis of liver disease of diverse aetiologies. This review explores the impact of HIFs on hepatocellular biology and inflammatory responses, highlighting the therapeutic potential of targeting HIFs for an array of liver pathologies.
    Full-text · Article · Dec 2014 · Journal of Hepatology
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    • "Further, work from our laboratory demonstrated that in vitro hypoxia can cause LC cells to produce genes involved in ECM production and remodelling including insulin-like growth factor 2 receptor (IGFR2) and macrophage migration inhibitory factor 1 (MIF) (Figure 4). The HIF families are the key regulators of the cell's adaptive response to hypoxia, and they control the expression of many genes involved in many cell processes, including fibrosis [125, 126]. HIF1α regulates gene expression through hypoxia response elements (HRE) present in the promoter regions of target genes. "
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    ABSTRACT: Glaucoma is an optic neuropathy that affects 60 million people worldwide. The main risk factor for glaucoma is increased intraocular pressure (IOP), this is currently the only target for treatment of glaucoma. However, some patients show disease progression despite well-controlled IOP. Another possible therapeutic target is the extracellular matrix (ECM) changes in glaucoma. There is an accumulation of ECM in the lamina cribrosa (LC) and trabecular meshwork (TM) and upregulation of profibrotic factors such as transforming growth factor β (TGF β ), collagen1 α 1 (COL1A1), and α -smooth muscle actin ( α SMA). One method of regulating fibrosis is through epigenetics; the study of heritable changes in gene function caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic mechanisms have been shown to drive renal and pulmonary fibrosis by upregulating profibrotic factors. Hypoxia alters epigenetic mechanisms through regulating the cell's response and there is a hypoxic environment in the LC and TM in glaucoma. This review looks at the role that hypoxia plays in inducing aberrant epigenetic mechanisms and the role these mechanisms play in inducing fibrosis. Evidence suggests that a hypoxic environment in glaucoma may induce aberrant epigenetic mechanisms that contribute to disease fibrosis. These may prove to be relevant therapeutic targets in glaucoma.
    Full-text · Article · Mar 2014 · Journal of Ophthalmology
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    • "Moon et al. demonstrated that in bile duct ligations-induced liver fibrosis animal model, liver underwent hypoxia, and HIF-1α was activated. After HIF-1α was deleted, bile duct ligations-induced collagen I and α-SMA expressions in the liver were significantly decreased [15]. Another study in alveolar epithelial cells showed that hypoxia-induced EMT was significantly attenuated by HIF-1α shRNA [16]. "
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    ABSTRACT: Transforming growth factor beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in kidney epithelial cells plays a key role in renal tubulointerstitial fibrosis in chronic kidney diseases. As hypoxia-inducible factor (HIF)-1α is found to mediate TGF-β1-induced signaling pathway, we tested the hypothesis that HIF-1α and its upstream regulator prolyl hydroxylase domain-containing proteins (PHDs) are involved in TGF-β1-induced EMT using cultured renal tubular cells. Our results showed that TGF-β1 stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker P-cadherin, and the increase in mesenchymal markers α-smooth muscle actin (α-SMA) and fibroblast-specific protein 1 (FSP-1). Meanwhile, we found that TGF-β1 time-dependently increased HIF-1α and that HIF-1α siRNA significantly inhibited TGF-β1-induced EMT, suggesting that HIF-1α mediated TGF-β1 induced-EMT. Real-time PCR showed that PHD1 and PHD2, rather than PHD3, could be detected, with PHD2 as the predominant form of PHDs (PHD1:PHD2=0.21:1.0). Importantly, PHD2 mRNA and protein, but not PHD1, was decreased by TGF-β1. Furthermore, over-expression of PHD2 transgene almost fully prevented TGF-β1-induced HIF-1α accumulation and EMT marker changes, indicating that PHD2 is involved in TGF-β1-induced EMT. Finally, Smad2/3 inhibitor SB431542 prevented TGF-β1-induced PHD2 decrease, suggesting that Smad2/3 may mediate TGF-β1-induced EMT through PHD2/HIF-1α pathway. It is concluded that TGF-β1 decreased PHD2 expression via a Smad-dependent signaling pathway, thereby leading to HIF-1α accumulation and then EMT in renal tubular cells. The present study suggests that PHD2/HIF-1α is a novel signaling pathway mediating the fibrogenic effect of TGF-β1, and may be a new therapeutic target in chronic kidney diseases.
    Preview · Article · Mar 2013 · Biochimica et Biophysica Acta
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