The aim of this work is to investigate the cellular and molecular mechanisms underlying the pathogenesis of progressive fibrosis of the kidney, which is the cardinal feature of chronic kidney disease. Although many progressive diseases are glomerular in origin, it is tubulointerstitial involvement that best predicts progression. In understanding how glomerular injury is transmitted to the tubulointerstitium, our group has suggested an important role for hypoxia; an idea formalised as the Chronic Hypoxia Hypothesis (Fine et al Kidney Int, 53 Suppl 65:S74-S78, 1998). In support of this hypothesis, in vivo, in a model of progressive renal disease, tissue hypoxia precedes renal scarring and in vitro studies have demonstrated that hypoxia (1% O2) can promote a fibrogenic phenotype in tubular epithelial cells and renal fibroblasts. Current studies are centred on understanding of the role of hypoxia in the pathogenesis of renal fibrosis. Specific areas of investigation include the mechanisms of hypoxic regulation of expression of fibrogenic genes; the control of fibroblast to myofibroblast differentiation; and the role of fibroblast-endothelial cell interactions in the pathogenesis of fibrosis. Another aspect of the work has been investigating the effects of isoprostanes (products of non-enymatic lipid peroxidation and validated markers of oxdative stress) on endothelial cell function. Our recent in vitro data has revealed a potential anti-inflammatory effect of isoprostanes in suppressing adhesion of monocytes to microvascular endothelial cells. On-going studies are investigating the mechanisms and mediators underlying this novel role for isoprostanes in the microvasculature.