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-κB and HIF-1α, key regulators of inflammation. These findings suggest that deficiency of VLDLR leads to retinal degeneration and inflammation.