title: Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury.
abstract: Acute kidney injury (AKI) due to ischemia is an important contributor to the progression of chronic kidney disease (CKD). Key mediators of cellular adaptation to hypoxia are oxygen-sensitive hypoxia-inducible factors (HIF), which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. While activation of HIF protects from ischemic cell death, HIF has been shown to promote fibrosis in experimental models of CKD. The impact of HIF activation on AKI-induced fibrosis has not been defined. Here, we investigated the role of pharmacologic HIF activation in AKI-associated fibrosis and inflammation. We found that pharmacologic inhibition of HIF prolyl hydroxylation before AKI ameliorated fibrosis and prevented anemia, while inhibition of HIF prolyl hydroxylation in the early recovery phase of AKI did not affect short- or long-term clinical outcome. Therefore, preischemic targeting of the PHD/HIF pathway represents an effective therapeutic strategy for the prevention of CKD resulting from AKI, and it warrants further investigation in clinical trials.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Pinelopi P
authors.initials: PP
authors.lastname: Kapitsinou
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jaffe
authors.forename: Mark
authors.initials: M
authors.lastname: Michael
authors.forename: Christina E
authors.initials: CE
authors.lastname: Swan
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Duffy
authors.forename: Connie L
authors.initials: CL
authors.lastname: Erickson-Miller
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis; D006900:Hydroxylation / Q000187:drug effects; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014991:Xylazine / Q000009:adverse effects
chemical_list: D004791:Enzyme Inhibitors; C485502:HIF-2 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D014157:Transcription Factors; D014991:Xylazine; D011393:Procollagen-Proline Dioxygenase