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

TLDR

Hypoxia is implicated in tissue fibrosis, but its underlying mechanisms remain poorly defined. The study aimed to determine whether HIF‑1α drives fibrosis by inactivating it in renal epithelial cells during unilateral ureteral obstruction in mice. HIF‑1α was inactivated in primary renal epithelial cells and proximal tubules of UUO kidneys using Cre‑loxP gene targeting. HIF‑1α promotes renal fibrosis by stimulating EMT and lysyl oxidase expression, and its deletion reduces fibrosis, collagen deposition, inflammation, and fibroblast markers; elevated HIF‑1α also correlates with tubulointerstitial injury in chronic kidney disease patients.

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-1α 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-1α enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1α 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-1α 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.