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

Yuefang Zhou, Thomas M. Bennett, Alan Shiels

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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 = <. 0.05) when compared with wild-type. A pathway analysis of up-regulated genes in the 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.

Original languageEnglish
Pages (from-to)1433-1442
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1862
Issue number8
DOIs
StatePublished - Aug 1 2016

Keywords

  • Cataract
  • Lens
  • Mouse
  • Oxidative stress
  • Unfolded protein response

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