The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease.

Over the past decade major advances have been made in our understanding of the molecular machinery that mammalian cells use to sense and to adapt to a low-oxygen environment. A critical mediator of cellular adaptation to hypoxia is hypoxia-inducible factor (HIF), a basic helix-loop-helix transcription factor that consists of an oxygen-sensitive alpha-subunit, HIF-alpha and a constitutively expressed beta-subunit, HIF-beta. Under conditions of normal oxygen tension, the HIF-alpha subunit is hydroxylated by specific prolyl-hydroxylases and targeted for rapid proteasomal degradation by the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition component of an E3-ubiquitin ligase. In a hypoxic environment or in the absence of functional VHL tumor suppressor protein irrespective of oxygen concentration, HIF-alpha is not degraded and translocates to the nucleus, where it dimerizes with HIF-beta to form transcriptionally active HIF. As a transcription factor, HIF is involved in the regulation of many biological processes that facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating genes that are involved in glucose uptake and energy metabolism, angiogenesis, erythropoiesis, cell proliferation and apoptosis, cell-cell and cell-matrix interactions, and barrier function. This review summarizes some of the most recent advances in the VHL/HIF field and discusses their relevance for pathogenesis and treatment of acute ischemic renal failure, renal fibrosis, and renal cancer.