Reduced liver fibrosis in hypoxia-inducible factor-1α-deficient mice

Abstract

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.

Cellular and molecular mechanisms in liver fibrogenesis

“…At the same time, MFs themselves are a source of VEGF-A and angiopoietin 1 and express related receptors (VEGFR2, Tie-2) in CLDs [83]; iv) experiments that have compared fibrogenesis progression in HIF-1α liver conditional knock-out mice and related wild type animals, revealed that hypoxia and HIF-1α expression precede fibrosis and that the liver specific silencing of HIF-1α resulted in a significant reduction of liver fibrosis [85]; v) experimental anti-angiogenic therapy, whatever the specific drug or therapeutic strategy employed, resulted in a significant inhibition of fibrogenic progression, being also effective in reducing inflammatory infiltrate, the number of α-SMA positive MFs as well as the increase in portal pressure and, with some drugs, to reduce also formation of porto-systemic collateral vessels and splanchnic vascularization in models of portal hypertensive animals or in cirrhotic animals (reviewed in [81,82,84]). …”

Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice

“…7 Particularly, HIF-1a is involved in the regulation of different profibrotic genes, 36 and HIF-1a knockout mice showed a significantly lower expression of collagen type I and a-SMA compared with wildtype controls after BDL. 6 Furthermore, HIF-1a has been shown to promote experimental renal fibrosis. 37 Our investigations show an upregulation of HIF-1a in liver tissue after BDL.…”

“…6 At 14 days after BDL, animals showed a significant reduction in hematocrit, red blood cells, and hemoglobin as shown in Figure 1. DPO reduced the drop of hemoglobin, resulting in less severe anemia.…”

“…5 One of the mechanisms by which liver injury stimulates the production of growth factors is hepatocellular hypoxia. Recently, Moon et al 6 reported that hypoxia-inducible factor (HIF)-1a is a critical regulator of profibrotic mediator production during the development of liver fibrosis. In line with this, many studies have reported a relationship between hypoxia and liver fibrosis in different experimental models.…”

“…In line with this, many studies have reported a relationship between hypoxia and liver fibrosis in different experimental models. [6][7][8] The renal glycoprotein hormone erythropoietin (Epo) has been well characterized as a primary mediator of the normal physiological response to hypoxia. Recombinant human Epo and its longer-acting hyperglycosylated analog, darbepoetin-a (DPO), are used to treat anemia associated with chronic diseases and non-myeloid cancer.…”