Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9

Abstract

Introduction Diabetic retinopathy remains one of the most feared complications of diabetes. Despite extensive research in the field, the molecular mechanism responsible for the development of this slow progressing disease remains unclear. In the pathogenesis of diabetic retinopathy, mitochondria are damaged and inflammatory mediators are elevated before the histopathology associated with the disease can be observed. Matrix metalloproteinases (MMPs) regulate a variety of cellular functions including apoptosis and angiogenesis. Diabetic environment stimulates the secretion of several MMPs that are considered to participate in complications, including retinopathy, nephropathy and cardiomyopathy. Patients with diabetic retinopathy and also animal models have shown increased MMP-9 and MMP-2 in their retina and vitreous. Recent research has shown that MMPs have dual role in the development of diabetic retinopathy; in the early stages of the disease (pre-neovascularization), MMP-2 and MMP-9 facilitate the apoptosis of retinal capillary cells, possibly via damaging the mitochondria, and in the later phase, they help in neovascularization. Areas covered This article reviews the literature to evaluate the role of MMPs, especially MMP-9, in the development of diabetic retinopathy, and presents existing evidence that the inhibitors targeted toward MMP-9, depending on the duration of diabetes at the times their administration could have potential to prevent the progression of this blinding disease, and protect the vision loss. Expert opinion Inhibitors of MMPs could have dual role: in the early stages of the diseases, inhibit capillary cell apoptosis, and if the disease has progressed to the angiogenic stage, inhibit the growth of new vessels.

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

“…Thus we believe that the most relevant results are those obtained by zymography since they represent the quantitative gelatinolytic effects of these proteins. Both gelatinases are involved in angiogeneis (24), and the diminution of MMP2 gelatinolytic activity by MB treatment identifies this gelatinase as one of the main targets of MB in the retina. MMP2 could be responsible for the inhibition of fibrosis and angiogenesis in the inner retina of animals treated with MB.…”

Proliferative Diabetic Retinopathy: An Overview of Vitreous Immune and Biomarkers

“…MMPs regulate many cellular functions including apoptosis, wound healing, and angiogenesis. In angiogenesis, MMPs increase VEGF production and remove physical barriers to new vessel growth [58,59]. MMPs are produced as a response to increased oxidative stress.…”

“…These are controlled by endogenous tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 regulates MMP-9 and TIMP-2 regulates MMP-2 [59]. Several studies suggest that MMPs are responsible for many diabetic complications, including cardiomyopathy, nephropathy, and retinopathy.…”

Contribution of epigenetics in diabetic retinopathy

“…In the pathogenesis of diabetic retinopathy, activation of matrix metalloproteinase-9 (MMP-9) is shown to damage mitochondria, and this initiates the apoptotic machinery [75,76]. MMP-9 is regulated by NF-B and the activation of NF-B is modulated by the acetylation of its p65 subunit.…”