TAT-mediated PRDX6 protein transduction protects against eye lens epithelial cell death and delays lens opacity.
A diminished level of endogenous antioxidant in cells/tissues is associated with reduced resistance to oxidative stress. Peroxiredoxin 6 (PRDX6), a protective molecule, regulates gene expression/function by controlling reactive oxygen species (ROS) levels. Using PRDX6 protein linked to TAT, the transduction domain from human immunodeficiency virus type 1 TAT protein, we demonstrated that PRDX6 was transduced into lens epithelial cells derived from rat or mouse lenses. The protein was biologically active, negatively regulating apoptosis and delaying progression of cataractogenesis by attenuating deleterious signaling. Lens epithelial cells from cataractous lenses bore elevated levels of ROS and were susceptible to oxidative stress. These cells harbored increased levels of active transforming growth factor (TGF)-beta 1 and of alpha-smooth muscle actin and beta ig-h3, markers for cataractogenesis. Importantly, cataractous lenses showed a 10-fold reduction in PRDX6 expression, whereas TGF-beta1 mRNA and protein levels were elevated. The changes were reversed, and cataractogenesis was delayed when PRDX6 was supplied. Results suggest that delivery of PRDX6 can postpone cataractogenesis, and this should be an effective approach to delaying cataracts and other degenerative diseases that are associated with increased ROS.
Kubo
Eri
E
Department of Ophthalmology, University of Fukui, Fukui, Japan.
Fatma
Nigar
N
Akagi
Yoshio
Y
Beier
David R
DR
Singh
Sanjay P
SP
Singh
Dhirendra P
DP
D000199:Actins / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002386:Cataract / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006861:Hydrogen Peroxide / Q000633:toxicity; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress; D054465:Peroxiredoxin VI / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D000099222:betaIG-H3 Protein
D000199:Actins; D000975:Antioxidants; D016326:Extracellular Matrix Proteins; D006861:Hydrogen Peroxide; D036341:Intercellular Signaling Peptides and Proteins; D016877:Oxidants; D054465:Peroxiredoxin VI; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099222:betaIG-H3 Protein; C558396:Acta2 protein, mouse; C119380:lens epithelium-derived growth factor; C498862:Acta2 protein, rat; C515983:Prdx6 protein, mouse; C515984:Prdx6 protein, rat