Oxidative stress and the development of diabetic retinopathy: contributory role of matrix metalloproteinase-2

Free Radic Biol Med. 2009 Jun 15;46(12):1677-85. doi: 10.1016/j.freeradbiomed.2009.03.024. Epub 2009 Apr 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cattle
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Retinopathy / enzymology*
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Dose-Response Relationship, Drug
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Free Radical Scavengers / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Glucose / pharmacology
  • Humans
  • Male
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Oxidative Stress*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Retina / enzymology
  • Retina / metabolism*
  • Retina / pathology*
  • Retinal Vessels / enzymology
  • Retinal Vessels / metabolism
  • Retinal Vessels / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Streptozocin
  • Superoxides / analysis
  • Superoxides / metabolism

Substances

  • Free Radical Scavengers
  • Matrix Metalloproteinase Inhibitors
  • RNA, Messenger
  • Superoxides
  • Streptozocin
  • Matrix Metalloproteinase 2
  • Glucose