Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition

Abstract

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.

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

“…Our finding of increased renal A 1 R, A 2A R, and A 2B R mRNA levels after UUO was in agreement with a previous report using a rat model [18], although A 3 R mRNA was undetectable, likely due to the very low level of expression of this receptor in mouse kidney [19]. Renal HIF-1α and ET-1 mRNA levels were also increased following UUO, as previously described [20,21]. Despite the similar renal injury and fibrosis of WT and CD39Tg mice, we found higher renal A 2A R mRNA levels at Fig.…”

HIF‐1α regulates EMT via the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

“…Recent studies have shown that HIF‐1α, as a profibrotic transcription factor, is involved in a variety of organs during the EMT process 47, 48. In our study, HIF‐1α protein expression increased in the early stage of PQ poisoning (2 hrs) sooner than HIF‐1α mRNA levels (12 hrs), which suggests that HIF‐1α is activated first at the translational or posttranslational level.…”

Hyperbaric Oxygen Potentiates Doxil Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells

“…Thus, lowering the content of collagen fibrils would facilitate drug deep penetration. [[qv: 15c]] Previous studies showed clear link between tumor hypoxia and the deposition of collagen fibrils: Higgins et al found that hypoxia‐induced connective tissue growth factor (CTGF) is mainly mediated by HIF‐1 α28 and similar results were revealed in renal system29 and in tumors 30. And CTGF acts as a critical regulator on collagen deposition in tumor tissue.…”