Photoreceptor degeneration and retinal inflammation induced by very low-density lipoprotein receptor deficiency.
Our previous studies have shown that very low-density lipoprotein receptor (VLDLR) is a negative regulator of the Wnt pathway. The present study showed that VLDLR gene knockout (Vldlr(-/-)) mice displayed impaired cone ERG responses at early ages. Immunostaining of mid-wavelength cones showed significantly decreased cone densities in the retina and shortened cone outer segments in Vldlr(-/-) mice. At older ages, Vldlr(-/-) mice displayed declined rod ERG responses, decreased layers of photoreceptor nuclei, reduced rhodopsin levels and decreased levels of 11-cis retinal, the chromophore of visual pigments. As shown by fluorescein angiography and permeability assay, Vldlr(-/-) mice had severe retinal vascular leakage. ZO-1, a tight junction protein, was down-regulated in Vldlr(-/-) mouse retinae, further supporting the impaired blood-retinal barrier. Double staining of pericytes and endothelial cells in retinal sections revealed that neovasculature in Vldlr(-/-) mice lacks pericyte coverage, suggesting impaired maturation of retinal vasculature in Vldlr(-/-) mice. Staining of adherent leukocytes in the retinal vasculature revealed significant leukostasis in Vldlr(-/-) mice. Moreover, Vldlr(-/-) mice displayed up-regulated expression of multiple pro-inflammatory factors and activated NF-kappaB and HIF-1 alpha, key regulators of inflammation. These findings suggest that deficiency of VLDLR leads to retinal degeneration and inflammation.
Chen
Ying
Y
Department of Cell Biology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Hu
Yang
Y
Moiseyev
Gennadiy
G
Zhou
Kevin K
KK
Chen
Danyang
D
Ma
Jian-xing
JX
D000818:Animals; D015536:Down-Regulation; D004596:Electroretinography; D005451:Fluorescein Angiography; D007249:Inflammation / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D012160:Retina / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; D010750:Phosphoproteins; D011973:Receptors, LDL; D017299:Rod Opsins; C569043:Tjp1 protein, mouse; C036053:VLDL receptor; D062826:Zonula Occludens-1 Protein; D012243:Rhodopsin