Figure 3. Potential profibrotic role of HIF activation in chronic kidney disease (CKD).

Shown is a simplified overview of functional and structural causes of hypoxia in CKD. As a result of hypoxia, activation of hypoxia-inducible factor (HIF) signaling in renal cells has the potential to promote renal fibrosis and to contribute to the progression of CKD as demonstrated experimentally in proximal tubule-specific HIF-1α knockout mice (unilateral uretal obstruction model) and in mice with increased tubular HIF-1α expression.^59,72 HIF may exert its profibrotic function by modulating cellular and molecular events that have key roles in the pathogenesis of renal fibrosis. These include extracellular matrix production and processing through regulation of matrix-modifying factors and enzymes, such as CTGF, PAI1, TIMP1, and MMPs, the modulation of EMT-triggering pathways, and inflammation.