Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice

Abstract

AbstractThe early and intermediate age-related macular degeneration (AMD) is characterized by the presence of drusen and pigmentary abnormalities in the retinal pigment epithelial (RPE) cells which form the outer blood retinal barrier (oBRB). Fluid leakage through the disrupted oBRB from the choroid to the neural retina has been implicated in the pathogenesis of AMD, however; the molecular mechanisms still remain unclear. The family of four transmembrane proteins, claudins are known to form tight junctions (TJs) in the oBRB. Nonetheless, there are few reports showing how they function in the oBRBin vivo. We found that claudin-1 is dominantly expressed in TJs of the mouse RPE. To investigate the role of claudin-1 in the RPE, we generated RPE-specificCldn1conditional knockout mice (Best1-Cre+/-Cldn1flox/floxmice:Cldn1cKO mice). Deficiency ofCldn1led to age-related lipid deposits such as subretinal drusenoid deposits (SDD), increased lipid droplets in the RPE, basal lamellar deposits (BlamD) and membranous debris in the Bruch’s membrane. In addition, pigmentary abnormalities such as RPE hypertrophy, multilayered-RPE cells, and ectopic pigment granules outside the RPE were observed inCldn1cKO mice. Our study provides new insights into the possible association of the TJ protein claudin-1 with lipid metabolism and cellular ageing in the RPE contributing to the early onset of AMD.