Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis, but the underlying mechanisms are not well defined. This study examines the role of hypoxia-inducible factor-1 (HIF-1) in the development of fibrosis in mice. Hif-1α was inactivated in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. The results showed 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, increased renal HIF-1α expression was associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, the study provides 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. The study also shows that HIF-1α is stabilized in progressive renal disease and that activation of HIF-1 may promote fibrosis by increasing expression of ECM-modifying factors and lysyl oxidases and by enhancing transition of epithelial cells toward a mesenchymal phenotype. The study highlights the role of HIF-1 in the progression of chronic kidney disease and suggests that targeting the HIF-1 pathway may be a potential therapeutic strategy for fibrosis.Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis, but the underlying mechanisms are not well defined. This study examines the role of hypoxia-inducible factor-1 (HIF-1) in the development of fibrosis in mice. Hif-1α was inactivated in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. The results showed 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, increased renal HIF-1α expression was associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, the study provides 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. The study also shows that HIF-1α is stabilized in progressive renal disease and that activation of HIF-1 may promote fibrosis by increasing expression of ECM-modifying factors and lysyl oxidases and by enhancing transition of epithelial cells toward a mesenchymal phenotype. The study highlights the role of HIF-1 in the progression of chronic kidney disease and suggests that targeting the HIF-1 pathway may be a potential therapeutic strategy for fibrosis.