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HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity
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DOI：10.1096/fj.201902240R.png)
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Abstract
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Pharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-alpha prolyl-4-hydroxylase domain (PHD) enzymes and HIF-alpha asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-alpha hydroxylase (broad spectrum), PHD-selective, and FIH-selective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO(2) than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO(2). Hence, the additional increase in pericellular pO(2) by pan- over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases.
Keywords:
anemia
hypoxia
2-oxoglutarate oxygenase inhibitor
prolyl hydroxylase inhibitor
Roxadustat
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