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

Hum Mol Genet. 2016 Sep 1;25(17):3810-3823. doi: 10.1093/hmg/ddw228. Epub 2016 Jul 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Disease Models, Animal
  • Erythropoietin / blood
  • Erythropoietin / metabolism
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney Diseases / genetics*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Lung / metabolism
  • Macular Degeneration / genetics*
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Mice
  • Muscle, Skeletal / metabolism
  • Myocardium / metabolism
  • Prolyl Hydroxylases / genetics*
  • Prolyl Hydroxylases / metabolism*
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology*
  • Tissue Distribution


  • Erythropoietin
  • Prolyl Hydroxylases
  • Hypoxia-Inducible Factor-Proline Dioxygenases