Initiation and Progression of Chronic Kidney Disease
Can We Definitively Test the Chronic Hypoxia Hypothesis?
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See related article, p 914–919
Fifteen years ago, Fine et al1 first presented the chronic hypoxia hypothesis about the progression of chronic kidney disease. Subsequent refinement of this hypothesis has led to the proposition that multiple forms of chronic kidney disease are, at least partly, driven by a vicious cycle of hypoxia, renal inflammation, and fibrosis, which inexorably leads to failure of glomerular filtration (Figure). Fine et al2 identified some of the critical pieces of evidence required to confirm or reject this hypothesis. The chronic hypoxia hypothesis predicts that renal tissue hypoxia can initiate signaling events that lead to renal damage and fibrosis.2 This part of the hypothesis has certainly been confirmed. As reviewed in detail by Mimura and Nangaku3 and by Fine et al2 themselves, hypoxia can lead to apoptosis, epithelial-to-mesenchyme transition, inhibition of the expression of collagenase and increased expression of metalloproteinase inhibitor 1, and stimulation of superoxide production via mitochondria, xanthine oxidase, and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase. However, it must also be said that much of the evidence to support these statements comes from in vitro studies, often using cultured cells, rather than from in vivo studies using experimental models of chronic kidney disease. Thus, we still have some way to go to understand the molecular mechanisms linking hypoxia and the progression of chronic kidney disease.