ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy
Diabetic retinopathy is one of the most common causes of blindness in North America. Several signaling mechanisms are activated secondary to hyperglycemia in diabetes, leading to activation of vasoactive factors. We investigated a novel pathway, namely extracellular signal regulated kinase 5 (ERK5)...
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| Format: | Article |
| Language: | English |
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Wiley
2010-01-01
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| Series: | Journal of Ophthalmology |
| Online Access: | http://dx.doi.org/10.1155/2010/465824 |
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| author | Yuexiu Wu Yufeng Zuo Rana Chakrabarti Biao Feng Shali Chen Subrata Chakrabarti |
| author_facet | Yuexiu Wu Yufeng Zuo Rana Chakrabarti Biao Feng Shali Chen Subrata Chakrabarti |
| author_sort | Yuexiu Wu |
| collection | DOAJ |
| description | Diabetic retinopathy is one of the most common causes of blindness in North America. Several signaling mechanisms are activated secondary to hyperglycemia in diabetes, leading to activation of vasoactive factors. We investigated a novel pathway, namely extracellular signal regulated kinase 5 (ERK5) mediated signaling, in modulating glucose-induced vascular endothelial growth factor (VEGF) expression.
Human microvascular endothelial cells (HMVEC) were exposed to glucose. In parallel, retinal tissues from streptozotocin-induced diabetic rats were examined after 4 months of follow-up. In HMVECs, glucose caused initial activation followed by deactivation of ERK5 and its downstream mediators myocyte enhancing factor 2C (MEF2C) and Kruppel-like factor 2 (KLF2) mRNA expression. ERK5 inactivation further led to augmented VEGF mRNA expression. Furthermore, siRNA mediated ERK5 gene knockdown suppressed MEF2C and KLF2 expression and increased VEGF expression and angiogenesis. On the other hand, constitutively active MEK5, an activator of ERK5, increased ERK5 activation and ERK5 and KLF2 mRNA expression and attenuated basal- and glucose-induced VEGF mRNA expression. In the retina of diabetic rats, depletion of ERK5, KLF2 and upregulation of VEGF mRNA were demonstrated.
These results indicated that ERK5 depletion contributes to glucose induced increased VEGF production and angiogenesis. Hence, ERK5 may be a putative therapeutic target to modulate VEGF expression in diabetic retinopathy. |
| format | Article |
| id | doaj-art-8ea1d9fbd98a451f84275c15e6db147f |
| institution | Kabale University |
| issn | 2090-004X 2090-0058 |
| language | English |
| publishDate | 2010-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Ophthalmology |
| spelling | doaj-art-8ea1d9fbd98a451f84275c15e6db147f2025-02-03T05:57:45ZengWileyJournal of Ophthalmology2090-004X2090-00582010-01-01201010.1155/2010/465824465824ERK5 Contributes to VEGF Alteration in Diabetic RetinopathyYuexiu Wu0Yufeng Zuo1Rana Chakrabarti2Biao Feng3Shali Chen4Subrata Chakrabarti5Department of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, N6A 5A5, CanadaDepartment of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, N6A 5A5, CanadaDepartment of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, N6A 5A5, CanadaDepartment of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, N6A 5A5, CanadaDepartment of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, N6A 5A5, CanadaDepartment of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, N6A 5A5, CanadaDiabetic retinopathy is one of the most common causes of blindness in North America. Several signaling mechanisms are activated secondary to hyperglycemia in diabetes, leading to activation of vasoactive factors. We investigated a novel pathway, namely extracellular signal regulated kinase 5 (ERK5) mediated signaling, in modulating glucose-induced vascular endothelial growth factor (VEGF) expression. Human microvascular endothelial cells (HMVEC) were exposed to glucose. In parallel, retinal tissues from streptozotocin-induced diabetic rats were examined after 4 months of follow-up. In HMVECs, glucose caused initial activation followed by deactivation of ERK5 and its downstream mediators myocyte enhancing factor 2C (MEF2C) and Kruppel-like factor 2 (KLF2) mRNA expression. ERK5 inactivation further led to augmented VEGF mRNA expression. Furthermore, siRNA mediated ERK5 gene knockdown suppressed MEF2C and KLF2 expression and increased VEGF expression and angiogenesis. On the other hand, constitutively active MEK5, an activator of ERK5, increased ERK5 activation and ERK5 and KLF2 mRNA expression and attenuated basal- and glucose-induced VEGF mRNA expression. In the retina of diabetic rats, depletion of ERK5, KLF2 and upregulation of VEGF mRNA were demonstrated. These results indicated that ERK5 depletion contributes to glucose induced increased VEGF production and angiogenesis. Hence, ERK5 may be a putative therapeutic target to modulate VEGF expression in diabetic retinopathy.http://dx.doi.org/10.1155/2010/465824 |
| spellingShingle | Yuexiu Wu Yufeng Zuo Rana Chakrabarti Biao Feng Shali Chen Subrata Chakrabarti ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy Journal of Ophthalmology |
| title | ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy |
| title_full | ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy |
| title_fullStr | ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy |
| title_full_unstemmed | ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy |
| title_short | ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy |
| title_sort | erk5 contributes to vegf alteration in diabetic retinopathy |
| url | http://dx.doi.org/10.1155/2010/465824 |
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