HIF signaling in CKD. Potential contributions of activated HIF signaling in resident kidney cells to the pathogenesis of renal fibrosis. As a result of hypoxia, HIF activation in renal epithelial cells is capable of promoting fibrosis as shown experimentally in proximal tubule-specific HIF-1α knockout mice (UUO model) and in mice with increased tubular HIF-1α expression.7,10 Epithelial HIF acts as a profibrotic transcription factor by modulating ECM production and processing through regulation of matrix-modifying factors and enzymes, such as CTGF, PAI1, TIMP1, and MMPs, and the modulation of EMT-triggering pathways. The role of non-epithelial HIF in the pathogenesis of renal fibrogenesis is not known. Abbreviations: CTGF, connective tissue growth factor; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; NO, nitric oxide; PAI1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; TIMP1, tissue-inhibitor of metalloproteinase 1.