| Diabetic retinopathy and signaling mechanism for activation of matrix metalloproteinase-9. | |
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MedLine Citation:
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PMID: 21567393 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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In the pathogenesis of diabetic retinopathy, H-Ras (a small molecular weight G-protein) and matrix metalloproteinase-9 (MMP9) act as pro-apoptotic, accelerating the apoptosis of retinal capillary cells, a phenomenon that predicts its development and the activation of MMP9 is under the control of H-Ras. The goal of this study is to elucidate the cellular mechanism by which H-Ras activates MMP9 culminating in the development of diabetic retinopathy. Using isolated retinal endothelial cells, the effect of regulation of H-Ras downstream signaling cascade, Raf-1, MEK and ERK, was investigated on glucose-induced activation of MMP9. In vitro results were confirmed in the retina obtained from diabetic mice manipulated for MMP9 gene, and also in the retinal microvasculature obtained from human donors with diabetic retinopathy. Regulation of Raf-1/MEK/ERK by their specific siRNAs and pharmacologic inhibitors prevented glucose-induced activation of MMP9 in retinal endothelial cells. In MMP9-KO mice, diabetes had no effect on retinal MMP9 activation, and H-Ras/Raf-1/MEK signaling cascade remained normal. Similarly, donors with diabetic retinopathy had increased MMP9 activity in their retinal microvessels, the site of histopathology associated with diabetic retinopathy, and this was accompanied by activated H-Ras signaling pathway (Raf-1/ERK). Collectively, these results suggest that Ras/Raf-1/MEK/ERK cascade has an important role in the activation of retinal MMP9 resulting in the apoptosis of its capillary cells. Understanding the upstream mechanism responsible for the activation of MMP9 should help identify novel molecular targets for future pharmacological interventions to inhibit the development/progression of diabetic retinopathy. J. Cell. Physiol. © 2011 Wiley-Liss, Inc. |
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Authors:
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Ghulam Mohammad; Renu A Kowluru |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-12 |
Journal Detail:
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Title: Journal of cellular physiology Volume: - ISSN: 1097-4652 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0050222 Medline TA: J Cell Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Wiley-Liss, Inc. |
Affiliation:
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Kresge Eye Institute, Wayne State University, Detroit, MI. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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