Hypoxic induction of<i>Ctgf</i>is directly mediated by Hif-1

Higgins, Debra F.; Biju, Mangatt P.; Akai, Yasuhiro; Wutz, Anton; Johnson, Randall S.; Haase, Volker H.

doi:10.1152/ajprenal.00245.2004

Cited by 257 publications

(213 citation statements)

References 70 publications

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“…CRT levels are increased during cellular stresses, including oxidative stress and hypoxia (25)(26)(27)(28). Oxidative stress is known to be involved in fibrogenesis in a number of disease processes, including liver, lung, and kidney fibrosis (67)(68)(69)(70)(71). Hypoxia also increases collagen production and deposition in some systems (72).…”

Section: Discussionmentioning

confidence: 99%

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Graham

Sweetwyne

Pallero

et al. 2010

Journal of Biological Chemistry

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Calreticulin (CRT), a chaperone and Ca2؉ regulator, enhances wound healing, and its expression correlates with fibrosis in animal models, suggesting that CRT regulates production of the extracellular matrix. However, direct regulation of collagen matrix by CRT has not been previously demonstrated. We investigated the role of CRT in the regulation of fibrillar collagen expression, secretion, processing, and deposition in the extracellular matrix by fibroblasts. Mouse embryonic fibroblasts deficient in CRT (CRT ؊/؊ MEFs) have reduced transcript levels of fibrillar collagen I and III and less soluble collagen as compared with wild type MEFs. Correspondingly, fibroblasts engineered to overexpress CRT have increased collagen type I transcript and protein. Collagen expression appears to be regulated by endoplasmic reticulum (ER) calcium levels and intracellular CRT, because thapsigargin treatment reduced collagen expression, whereas addition of exogenous recombinant CRT had no effect. CRT ؊/؊ MEFs exhibited increased ER retention of collagen, and collagen and CRT were co-immunoprecipitated from isolated cell lysates, suggesting that CRT is important for trafficking of collagen through the ER. CRT ؊/؊ MEFs also have reduced type I procollagen processing and deposition into the extracellular matrix. The reduced collagen matrix deposition is partly a consequence of reduced fibronectin matrix formation in the CRT-deficient cells. Together, these data show that CRT complexes with collagen in cells and that CRT plays critical roles at multiple stages of collagen expression and processing. These data identify CRT as an important regulator of collagen and suggest that intracellular CRT signaling plays an important role in tissue remodeling and fibrosis.Calreticulin (CRT), 3 also known as the C1q receptor, is an endoplasmic reticulum (ER) chaperone, and a modulator of intracellular calcium signaling. CRT also is a multifunctional protein that is present in numerous cellular compartments, including the ER, cytoplasm, nucleus, at the cell surface, and as a released protein (1-5). There is evidence to suggest the involvement of CRT in tissue remodeling and wound healing. In a porcine dermal wound healing model, topical application of purified CRT increases the rate of wound healing and wound tensile strength (6). Proteomic data show up-regulation of CRT expression with fibrosis in a rat model of unilateral ureteric obstruction kidney fibrosis and in a mouse model of bleomycininduced lung fibrosis (7). The mechanisms by which CRT regulates tissue remodeling are not well understood, although fibronectin matrix deposition and modulation of cell adhesion, motility, proliferation, and matrix metalloproteinase expression have been implicated (6, 8 -13).CRT has effects on the extracellular matrix (ECM) and cellular responses to the ECM. Fibroblasts overexpressing CRT have increased fibronectin mRNA, protein, and matrix deposition, and cells lacking CRT express less fibronectin than wild type cells (9,14). CRT in the ER is thought to reg...

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Section: Discussionmentioning

confidence: 99%

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Graham

Sweetwyne

Pallero

et al. 2010

Journal of Biological Chemistry

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“…Hypoxia has been shown to increase the production of collagen as well as profibrogenic factors like plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1, and connective tissue growth factor through an HIF-mediated transcriptional response (33)(34)(35). Furthermore, hypoxia and TGF-β have been shown to synergize with regard to the production of certain collagens in fibroblasts (36,37).…”

Section: Discussionmentioning

confidence: 99%

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Stockmann

Kerdiles

Nomaksteinsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/β-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.

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“…On the other hand, activation of the HIF system in podocytes induced by VHL knockout was recently reported to result activation and proliferation of podocytes and resulted in a pathology resembling rapid progressive glomerulonephritis [46]. Moreover, there is evidence that HIF may also promote renal fibrosis [47] and thus the net balance of beneficial and potential adverse effects of HIF activation may have to be carefully established under conditions of long-term intervention.…”

Section: Chronic Kidney Diseasementioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

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Hypoxic induction ofCtgfis directly mediated by Hif-1

Cited by 257 publications

References 70 publications

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Hypoxia and the HIF system in kidney disease

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