title: Inactivation of prolyl hydroxylase domain (PHD) protein by epigallocatechin (EGCG) stabilizes hypoxia-inducible factor (HIF-1α) and induces hepcidin (Hamp) in rat kidney.
abstract: HIF-1α plays a key role in iron uptake and transport in the liver, whose activity is tightly linked to the repression of hepcidin (Hamp). Hamp prevents intestinal iron uptake and cellular efflux by negatively modulating ferroportin. Hamp is also expressed in the kidneys, where transcriptional control by HIF-1α remains poorly understood. We show that the administration of epigallocatechin gallate (EGCG) results in a considerable Hamp expression in rat kidneys. We also provide evidence to show that EGCG inhibited prolyl hydroxylase (PHD) activity, essential for HIF-1α degradation in vivo and in vitro. Rats that were dosed with EGCG (60 mg/kg, intraperitoneal) over a 7 day time course stabilized HIF-1α protein in kidney tissues. Interestingly, Hamp gene expression was induced, even after subjecting rats to a 4h hypoxia treatment (8% oxygen). Using Hep3B cells, we determined that EGCG conferred its inhibitory action by complexing with PHD, altering its catalytic iron center and thus preventing HIF-1α hydroxylation. These data demonstrate EGCG's therapeutic potential in modulating hepcidin expression in diseases associated with altered iron metabolism.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Dominador J
authors.initials: DJ
authors.lastname: Manalo
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
authors.forename: Evi
authors.initials: E
authors.lastname: Struble
authors.forename: Bindu
authors.initials: B
authors.lastname: Abraham
authors.forename: Abdu I
authors.initials: AI
authors.lastname: Alayash
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D019189:Iron Metabolism Disorders / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D023181:Antimicrobial Cationic Peptides; C578703:Hamp protein, rat; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002392:Catechin; D011393:Procollagen-Proline Dioxygenase; C580731:Egln1 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C057580:gallocatechol