Role of the unfolded protein response (UPR) in cataract formation.
Cataract is a multifactorial disease, and a large variety of stressors induce cataracts. Many cataractogenic stressors and endoplasmic reticulum (ER) stressors induce the unfolded protein response (UPR) in various cell types. The UPR is known to produce reactive oxygen species (ROS) prior to the inducement of apoptosis. We investigated whether ER stressors induce the UPR in lens epithelial cells (LECs) or whole rat lenses. Our results showed that higher levels of ER stressors activated Bip/GRP78, ATF4, and caspase-12. In addition, ROS were produced, free glutathione was decreased, and apoptosis was induced. LECs in the mitotic zone were the most susceptible to the UPR while the central LECs were the most resistant. The UPR induced the production of ROS in the ER and probably in the mitochondria. The detectable ROS production in cultured lenses is limited to the epithelial cells. These findings indicate that ER stressors induce the UPR in LECs with and without the induction of apoptosis, and we conclude that the UPR is probably one of the initiating factors of many types of cataracts.
Ikesugi
Kengo
K
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, 985840 Nebraska Medical Center, Omaha, NE 68198-5840, USA.
Yamamoto
Ryoko
R
Mulhern
Michael L
ML
Shinohara
Toshimichi
T
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002386:Cataract / Q000378:metabolism*; D002461:Cell Line, Transformed; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism*; D018832:Molecular Chaperones; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D046509:Tissue Culture Techniques; D014415:Tunicamycin / Q000494:pharmacology
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007476:Ionophores; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D006710:Homocysteine; D014415:Tunicamycin; D000001:Calcimycin; D005978:Glutathione; D005947:Glucose