Lack of P4H-TM in mice results in age-related retinal and renal alterations

Research output: Contribution to journalArticleScientificpeer-review

Researchers

  • Henri Leinonen
  • Maarit Rossi
  • Antti Salo
  • Päivi Tiainen
  • Jaana Hyvärinen
  • Marja Pitkänen
  • Raija Sormunen
  • Ilkka Miinalainen
  • Chi Zhang
  • Raija Soininen
  • Kari Kivirikko
  • Ari Koskelainen
  • Heikki Tanila
  • Johanna Myllyharju
  • Peppi Koivunen

Research units

  • University of Eastern Finland
  • University of Oulu

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.

Details

Original languageEnglish
JournalHUMAN MOLECULAR GENETICS
Volume25
Issue number17
Publication statusPublished - 27 Jul 2016
MoE publication typeA1 Journal article-refereed

ID: 10321075