title: Lack of P4H-TM in mice results in age-related retinal and renal alterations.
abstract: Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney. P4h-tm-/-mice were fertile and had a normal life span. Lack of P4h-tm stabilized HIF-1α in cortical neurons under normoxia, while in hypoxia it increased the expression of certain HIF target genes in tissues with high endogenous P4h-tm expression levels more than in wild-type mice. Renal erythropoietin levels increased in P4h-tm-/-mice with aging, but the resulting ∼2-fold increase in erythropoietin serum levels did not lead to erythrocytosis. Instead, accumulation of lipid-containing lamellar bodies in renal tubuli was detected in P4h-tm-/-mice with aging, resulting in inflammation and fibrosis, and later glomerular sclerosis and albuminuria. Lack of P4h-tm was associated with retinal thinning, rosette-like infoldings and drusen-like structure accumulation in RPE with aging, as is characteristic of AMD. Photoreceptor recycling was compromised, and electroretinograms revealed functional impairment of the cone pathway in adult P4h-tm-/-mice and cone and rod deficiency in middle-aged mice. P4H-TM is therefore imperative for normal vision, and potentially a novel candidate for age-induced diseases, such as AMD.
authors.affiliation: A.I. Virtanen Institute, Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Henri
authors.initials: H
authors.lastname: Leinonen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Antti M
authors.initials: AM
authors.lastname: Salo
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Tiainen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Hyvärinen
authors.affiliation: Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, FI-00076 Aalto, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Pitkänen
authors.affiliation: Biocenter Oulu, University of Oulu, FIN-90014 Oulu, Finland.|Department of Pathology, University of Oulu and Oulu University Hospital, FIN-90014 Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Biocenter Oulu, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Miinalainen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Biocenter Oulu, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Soininen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Kari I
authors.initials: KI
authors.lastname: Kivirikko
authors.affiliation: Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, FI-00076 Aalto, Finland.
authors.forename: Ari
authors.initials: A
authors.lastname: Koskelainen
authors.affiliation: A.I. Virtanen Institute, Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland peppi.koivunen@oulu.fi.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000097:blood / Q000378:metabolism; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D014018:Tissue Distribution
chemical_list: D004921:Erythropoietin; D064828:Prolyl Hydroxylases; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases