Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis

A Laitala, E Aro, G Walkinshaw, JM Mäki… - Blood, The Journal …, 2012 - ashpublications.org
A Laitala, E Aro, G Walkinshaw, JM Mäki, M Rossi, M Heikkilä, ER Savolainen, M Arend…
Blood, The Journal of the American Society of Hematology, 2012ashpublications.org
An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to
hydroxylate the α subunit of the hypoxia-inducible factor (HIF) in vitro and in cultured cells,
but nothing is known about its roles in mammalian erythropoiesis. We studied such roles
here by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm−/− mice. This caused larger
increases in serum Epo concentration and kidney but not liver Hif-1α and Hif-2α protein and
Epo mRNA levels than in wild-type mice, while the liver Hepcidin mRNA level was lower in …
Abstract
An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α subunit of the hypoxia-inducible factor (HIF) in vitro and in cultured cells, but nothing is known about its roles in mammalian erythropoiesis. We studied such roles here by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm−/− mice. This caused larger increases in serum Epo concentration and kidney but not liver Hif-1α and Hif-2α protein and Epo mRNA levels than in wild-type mice, while the liver Hepcidin mRNA level was lower in the P4h-tm−/− mice than in the wild-type. Similar, but not identical, differences were also seen between FG-4497–treated Hif-p4h-2 hypomorphic (Hif-p4h-2gt/gt) and Hif-p4h-3−/− mice versus wild-type mice. FG-4497 administration increased hemoglobin and hematocrit values similarly in the P4h-tm−/− and wild-type mice, but caused higher increases in both values in the Hif-p4h-2gt/gt mice and in hematocrit value in the Hif-p4h-3−/− mice than in the wild-type. Hif-p4h-2gt/gt/P4h-tm−/− double gene-modified mice nevertheless had increased hemoglobin and hematocrit values without any FG-4497 administration, although no such abnormalities were seen in the Hif-p4h-2gt/gt or P4h-tm−/− mice. Our data thus indicate that P4H-TM plays a role in the regulation of EPO production, hepcidin expression, and erythropoiesis.
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