Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition
Open accessAbstract
Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.
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Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types.
“Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types”
From Hypoxic control of metastasis (2016) · cites this paper as [67]
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“We note that HIF-1α has also been reported to promote epithelial–mesenchymal transition (EMT) in several types of cancer by modulating one or more EMT-associated genes.[53] Moreover, in this study, we demonstrated that TGF-β1 neutralization completely abolishes platelet-induced HIF-1α expression in endometriotic cells.”
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- Authors
- Higgins, D. F., Kimura, K., Bernhardt, W. M., Shrimanker, N., Akai, Y., Hohenstein, B., Saito, Y., Johnson, R. S., Kretzler, M., Cohen, C. D., Eckardt, K.-U., Iwano, M., & Haase, V. H.
- Affiliations
- University of Pennsylvania (US)
- Nara Medical University (JP)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of California San Diego (US)
- University of Michigan (US)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Haase, Volker H.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-11-21
- Volume
- 117
- Issue
- 12
- Pages
- 3810-20
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2082142
- OpenAlex
- W2053470746
- Cited by
- 976
- References
- 4
- Citations by year
- 2026: 13 · 2025: 41 · 2024: 31 · 2023: 55 · 2022: 67 · 2021: 50 · 2020: 58 · 2019: 61 · 2018: 51 · 2017: 70 · 2016: 61 · 2015: 57 · 2014: 68 · 2013: 54 · 2012: 58
- FWCI
- 28.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- University of Pennsylvania (P30-DK50306)
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072037, R01DK079912, R21DK072037, P30DK50306, P30DK050306)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- hypoxia, HIF-1α, epithelial-mesenchymal transition, renal fibrosis, tubulointerstitial fibrosis, lysyl oxidase, epithelial cell migration, chronic kidney disease, unilateral ureteral obstruction, interstitial collagen deposition, S100A4, extracellular matrix
- MeSH terms
- S100 Calcium-Binding Protein A4, Animals, Hypoxia, Calcium-Binding Proteins, Cell Movement, Chronic Disease, Collagen, Epithelial Cells, Extracellular Matrix, Fibrosis, Kidney Tubules, Proximal, Protein-Lysine 6-Oxidase, S100 Proteins, Ureteral Obstruction, Signal Transduction, Cell Hypoxia, Up-Regulation, Mice, Knockout, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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