Lens ER-stress response during cataract development in Mip-mutant mice.

Abstract Major intrinsic protein (MIP) is a functional water-channel (AQP0) that also plays a key role in establishing lens fiber cell architecture. Genetic variants of MIP have been associated with inherited and age-related forms of cataract; however, the underlying pathogenic mechanisms are unclear. Here we have used lens transcriptome profiling by microarray-hybridization and qPCR to identify pathogenic changes during cataract development in Mip -mutant ( Lop /+) mice. In postnatal Lop /+ lenses (P7) 99 genes were up-regulated and 75 were down-regulated (> 2-fold, p =  Lop /+ lens (P7) was consistent with endoplasmic reticulum (ER)-stress and activation of the unfolded protein response (UPR). The most up-regulated UPR genes (> 4-fold) in the Lop /+ lens included Chac1  >  Ddit3  >  Atf3  >  Trib3  >  Xbp1 and the most down-regulated genes (> 5-fold) included two anti-oxidant genes, Hspb1 and Hmox1 . Lop /+ lenses were further characterized by abundant TUNEL-positive nuclei within central degenerating fiber cells, glutathione depletion, free-radical overproduction, and calpain hyper-activation. These data suggest that Lop /+ lenses undergo proteotoxic ER-stress induced cell-death resulting from prolonged activation of the Eif2ak3 / Perk - Atf4 - Ddit3 - Chac1 branch of the UPR coupled with severe oxidative-stress.