Oxidative stress and the development of diabetic retinopathy: contributory role of matrix metalloproteinase-2.
Matrix metalloproteinases (MMPs) degrade extracellular matrix and regulate many functions including cell signaling. Oxidative stress is implicated in the development of diabetic retinopathy, and MMP-2, the most ubiquitous member of the MMP family, is sensitive to oxidative stress. This study aimed to determine the regulation of MMP-2 by oxidative stress in the development of diabetic retinopathy and the role of MMP-2 in the apoptosis of retinal capillary cells. The effects of mitochondrial superoxide scavenger on glucose-induced alterations in MMP-2, and its proenzyme activator MT1-MMP and physiological inhibitor TIMP-2, were determined in retinal endothelial cells, and the regulation of their glucose-induced accelerated apoptosis by the inhibitors of MMP-2 was accessed. To confirm in vitro results, the effects of antioxidant supplementation on MMP-2, MT1-MMP, and TIMP-2 were investigated in the retina of streptozotocin-induced diabetic rats. Glucose-induced activation of retinal capillary cell MMP-2 and MT1-MMP and decrease in TIMP-2 were inhibited by superoxide scavengers, and their accelerated apoptosis was prevented by the inhibitors of MMP-2. Antioxidant therapies, which have been shown to inhibit oxidative stress, capillary cell apoptosis, and retinopathy in diabetic rats, ameliorated alterations in retinal MMP-2 and its regulators. Thus, MMP-2 has a proapoptotic role in the loss of retinal capillary cells in diabetes, and the activation of MMP-2 is under the control of superoxide. This suggests a possible use of MMP-2-targeted therapy to inhibit the development of diabetic retinopathy.
Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA. rkowluru@med.wayne.edu
Renu A
RA
Kowluru
Mamta
M
Kanwar
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012160:Retina / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D012171:Retinal Vessels / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin; D013481:Superoxides / Q000032:analysis / Q000378:metabolism
D016166:Free Radical Scavengers; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D013481:Superoxides; D013311:Streptozocin; D020778:Matrix Metalloproteinase 2; D005947:Glucose