Induction of hypoxia inducible factor (HIF-1alpha) in rat kidneys by iron chelation with the hydroxypyridinone, CP94.

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Baek JH, Reiter CE, Manalo DJ, Buehler PW, Hider RC, Alayash AI

Induction of hypoxia inducible factor (HIF-1alpha) in rat kidneys by iron chelation with the hydroxypyridinone, CP94.

Biochim Biophys Acta. 2011 Apr-Jun;1809(4-6):262-8. doi: 10.1016/j.bbagrm.2011.04.010. Epub 2011 May 1.

PubMed ID

21558026 [ View in PubMed

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Abstract

Hypoxia inducible factor (HIF-1alpha) is a master regulator of tissue adaptive responses to hypoxia whose stability is controlled by an iron containing prolyl hydroxylase domain (PHD) protein. A catalytic redox cycle in the PHD's iron center that results in the formation of a ferryl (Fe(+4)) intermediate has been reported to be responsible for the hydroxylation and subsequent degradation of HIF-1alpha under normoxia. We show that induction of HIF-1alpha in rat kidneys can be achieved by iron reduction by the hydroxypyridin-4 one (CP94), an iron chelator administered intraperitoneally in rats. The extent of HIF protein stabilization as well as the expression of HIF target genes, including erythropoietin (EPO), in kidney tissues was comparable to those induced by known inhibitors of the PHD enzyme, such as desferrioxamine (DFO) and cobalt chloride (CoCl(2)). In human kidney cells and in vitro PHD activity assay, we were able to show that the HIF-1alpha protein can be stabilized by addition of CP94. This appears to inactivate PHD; and thus prevents the hydroxylation of HIF-1alpha. In conclusion, we have identified the inhibition of iron-binding pocket of PHD as an underlying mechanism of HIF induction in vivo and in vitro by a bidentate hydroxypyridinone.