期刊
HUMAN MOLECULAR GENETICS
卷 25, 期 17, 页码 3810-3823出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw228
关键词
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资金
- Academy of Finland [120156, 140765, 218129, 200471, 202469]
- Center of Excellence Grant [251314]
- S. Juselius Foundation
- Emil Aaltonen Foundation
- Jane and Aatos Erkko Foundation
- FibroGen, Inc.
- Academy of Finland (AKA) [120156, 140765, 218129, 120156, 200471, 140765, 200471, 202469, 218129, 202469] Funding Source: Academy of Finland (AKA)
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-1a 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 similar to 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.
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