Hypoxia has been proposed to play a crucial role in the development of tissue fibrosis, but the underlying mechanisms are not well understood. This study investigates the role of hypoxia-inducible factor-1 (HIF-1) in fibrosis development in mice. Using Cre-loxP-mediated gene targeting, the authors found that HIF-1α enhanced epithelial-to-mesenchymal transition (EMT) in primary renal epithelial cells and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of HIF-1α inhibited tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) kidneys, reducing interstitial collagen deposition, inflammatory cell infiltration, and the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Additionally, increased renal HIF-1α expression was associated with tubulointerstitial injury in patients with chronic kidney disease. These findings provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells promotes fibrogenesis by increasing the expression of extracellular matrix-modifying factors and lysyl oxidase genes and facilitating EMT.Hypoxia has been proposed to play a crucial role in the development of tissue fibrosis, but the underlying mechanisms are not well understood. This study investigates the role of hypoxia-inducible factor-1 (HIF-1) in fibrosis development in mice. Using Cre-loxP-mediated gene targeting, the authors found that HIF-1α enhanced epithelial-to-mesenchymal transition (EMT) in primary renal epithelial cells and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of HIF-1α inhibited tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) kidneys, reducing interstitial collagen deposition, inflammatory cell infiltration, and the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Additionally, increased renal HIF-1α expression was associated with tubulointerstitial injury in patients with chronic kidney disease. These findings provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells promotes fibrogenesis by increasing the expression of extracellular matrix-modifying factors and lysyl oxidase genes and facilitating EMT.