HIF in Kidney Disease and Development

Adenosine Generation and Signaling during Acute Kidney Injury

“…13,14 It is well established that levels of adenosine dramatically increase in the extracellular space during periods of renal hypoxia 75 and ischemia. 76 For instance, during periods of renal ischemia, levels of adenosine in the kidney rise approximately fivefold.…”

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

“…Under normoxia, HIF-α subunits are constantly produced, but not allowed to accu mulate, since they are rapidly hydroxylated by oxygen-dependent HIF prolyl-4-hydroxylase domain enzymes (PHD), subsequently captured by the ubiquitin ligase Von-Hippel-Lindau protein (VHL), and degraded by the proteasome. Under oxygen defi ciency, PHD activity is reduced, HIF-α accumulates within the cytosol, αβ-dimers are formed, translocate into the nucleus, and bind to hypoxia response elements (HREs) in the promoter enhancer region of genes, which are subsequently transactivated [2][3][4].…”

“…Many of the HIFtarget genes constitute a reasonable adaptation to hypoxia, such as erythropoiesis (EPO), increased glucose uptake (glucose transporter-1), switch of metabolism to glycolysis (several key enzymes of glycolysis), increased lactate utilization (lactate dehydrogenase), angiogenesis (VEGF), vasodilation (inducible nitric oxide synthase [iNOS]), removal of protons (carbonic anhydrase 9), and scavenging of free radicals (HO-1) [2][3][4].…”

“…Hypoxia-mimetic PHD inhibitors (PHD-I) are potent newly developed measures in the induction of the HIF-HRE axis. For simplicity, numerous additional factors involved in HIF regulation and action are not included in this cartoon and the reader is referred to comprehensive reviews such as references [3,12]. [8].…”

“…Recent discoveries underscore a host of additional compound biological pathways, associated with the regulation of the HIF signal, including the control of HIF synthesis, HIF controlling PHD synthesis, putative competing/intervening impacts of HIF-3α and PHD-3, cross-talk of HIF and other key regulators of gene expression (STAT, p-300 and others), further modifi cation of HIF-α activity at the level of DNA hypoxiaresponsive elements by small ubiquitin-like modifi ers (SUMO) and factor inhibiting HIF (FIH), and the eff ect of reactive oxygen species (ROS), NO and Krebs cycle metabolites on HIF degradation. Th ese complex pathways are beyond the scope of this review, and the interested reader is referred to additional references [3,5,[12][13][14][15][16][17][18].…”