The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina
This study was conducted to determine the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a time-dependent manner and the effect of extracellular-signal-regulated kinases-1/2 (ERK1/2) inhibition on the expressions of MMP-9, TIMP-1, and inflamm...
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2013/658548 |
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| author | Ghulam Mohammad Mohammad Mairaj Siddiquei Mohammad Imtiaz Nawaz Ahmed M. Abu El-Asrar |
| author_facet | Ghulam Mohammad Mohammad Mairaj Siddiquei Mohammad Imtiaz Nawaz Ahmed M. Abu El-Asrar |
| author_sort | Ghulam Mohammad |
| collection | DOAJ |
| description | This study was conducted to determine the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a time-dependent manner and the effect of extracellular-signal-regulated kinases-1/2 (ERK1/2) inhibition on the expressions of MMP-9, TIMP-1, and inflammatory biomarkers in the retinas of diabetic rats. The expression of MMP-9 was quantified by zymography, and the mRNA level of MMP-9 and TIMP-1 was quantified by RT-PCR. The expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) was examined by Western blot analysis. MMP-9 expression was significantly higher in diabetic rat retinas compared to controls at all time points.TIMP-1 expression was nonsignificantly upregulated at 1week of diabetes and was significantly downregulated at 4 and 12 weeks of diabetes. Intravitreal administration of the ERK1/2 inhibitor U0126 prior to induction of diabetes decreased ERK1/2 activation, attenuated diabetes-induced upregulation of MMP-9, iNOS, IL-6, and TNF-α and upregulated TIMP-1 expression. In MMP-9 knockout mice, diabetes had no effect on retinal iNOS expression and its level remained unchanged. These data provide evidence that ERK1/2 signaling pathway is involved in MMP-9, iNOS, IL-6, and TNF-α induction in diabetic retinas and suggest that ERK1/2 can be a novel therapeutic target in diabetic retinopathy. |
| format | Article |
| id | doaj-art-1f718a4e06534a79a8eb1d9e9f8c84f2 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-1f718a4e06534a79a8eb1d9e9f8c84f22025-02-03T01:30:13ZengWileyJournal of Diabetes Research2314-67452314-67532013-01-01201310.1155/2013/658548658548The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the RetinaGhulam Mohammad0Mohammad Mairaj Siddiquei1Mohammad Imtiaz Nawaz2Ahmed M. Abu El-Asrar3Department of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi ArabiaDepartment of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi ArabiaDepartment of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi ArabiaDepartment of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi ArabiaThis study was conducted to determine the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a time-dependent manner and the effect of extracellular-signal-regulated kinases-1/2 (ERK1/2) inhibition on the expressions of MMP-9, TIMP-1, and inflammatory biomarkers in the retinas of diabetic rats. The expression of MMP-9 was quantified by zymography, and the mRNA level of MMP-9 and TIMP-1 was quantified by RT-PCR. The expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) was examined by Western blot analysis. MMP-9 expression was significantly higher in diabetic rat retinas compared to controls at all time points.TIMP-1 expression was nonsignificantly upregulated at 1week of diabetes and was significantly downregulated at 4 and 12 weeks of diabetes. Intravitreal administration of the ERK1/2 inhibitor U0126 prior to induction of diabetes decreased ERK1/2 activation, attenuated diabetes-induced upregulation of MMP-9, iNOS, IL-6, and TNF-α and upregulated TIMP-1 expression. In MMP-9 knockout mice, diabetes had no effect on retinal iNOS expression and its level remained unchanged. These data provide evidence that ERK1/2 signaling pathway is involved in MMP-9, iNOS, IL-6, and TNF-α induction in diabetic retinas and suggest that ERK1/2 can be a novel therapeutic target in diabetic retinopathy.http://dx.doi.org/10.1155/2013/658548 |
| spellingShingle | Ghulam Mohammad Mohammad Mairaj Siddiquei Mohammad Imtiaz Nawaz Ahmed M. Abu El-Asrar The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina Journal of Diabetes Research |
| title | The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina |
| title_full | The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina |
| title_fullStr | The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina |
| title_full_unstemmed | The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina |
| title_short | The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina |
| title_sort | erk1 2 inhibitor u0126 attenuates diabetes induced upregulation of mmp 9 and biomarkers of inflammation in the retina |
| url | http://dx.doi.org/10.1155/2013/658548 |
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