| Status | 已發表Published |
| Regulation of retinal blood barrier by TNF alpha convertase, ADAM17, and its implication in diabetic macular edema | |
| Gutsaeva, D.; Hussein, K.; Lamoke, F.; Kwok, H. F.; Solomon, A.; Martin, P. M.; Al-Shabrawey, M. A.; Bartoli, M. | |
| 2016-09-01 | |
| Source Publication | Investigative Ophthalmology & Visual Science
 |
| Pages | 3226--- |
| Publication Place | Rockville, MD |
| Publisher | The Association for Research in Vision and Ophthalmology |
| Abstract | Purpose : Tumor necrosis factor alpha convertase (TACE/ADAM17) is an important regulator of inflammatory and neuroprotective responses due to its sheddase activity towards cytokines, cytokine receptors and adhesion molecules. We have previously demonstrated that TACE/ADAM17 expression and activity are up-regulated in the diabetic rat and human retina. Here we aimed to further investigate TACE/ADAM17 implication and mode of action on paracellular permeability, a critical target of hyperglycemia and a pathogenic feature of diabetic retinopathy (DR). Methods : Paracellular permeability in human and bovine retinal endothelial cells (HuREC and BREC, respectively) in cultures was assessed by the electrical cell-substrate impedance sensing (ECIS) technique in response to TNF alpha (20-100 ng/ml for 24 hours) and high glucose (HG; 25mM for 48 hours, conditioned medium). Western blotting and immunohistochemistry analyses were performed to assess expression levels and immunolocalization of the tight junction protein junction adhesion molecule A (JAM-A), a direct substrate of TACE/ADAM17. Inhibition of TACE/ADAM17 was achieved using a chemical inhibitor AL-4-1A1 (1 µM) or a human anti-ADAM17 inhibitory antibody D1(A12) (0.5 µM). Results : HG and TNF alpha, given alone or in combination, promoted a significant decrease in paracellular permeability, as determined by the reduction of trans-endothelial electrical resistance in HuREC and BREC monolayers. Treatment of the cells with AL-4-1A1 inhibitor or anti-ADAM17 antibodies halted these effects and significantly restored barrier function. In addition, we have found that JAM-A-specific epifluorescence was decreased in cells stimulated with TNF alpha or HG, given alone or in combination. However, blockade of AL-4-1A1 activity using AL-4-1A1 inhibitor AL-4-1A1 or anti-ADAM17 antibodies restored normal JAM-A-specific epifluorescence. Conclusions : The sum of the obtained results directly implicates TACE/ADAM17 in TNF alpha and HG-induced paracellular permeability through a mechanism involving shedding of JAM-A from the cells surface and, potentially, redistribution of intercellular junctional proteins. These data further support a role for TACE/ADAM17 in DR pathogenesis and suggest the use of specific inhibitors of this convertase as potential treatment for diabetic macular edema and DR. |
| Keyword | ADAM17/TACE diabetic macular edema and DR |
| URL | View the original |
| Language | 英語English |
| The Source to Article | PB_Publication |
| PUB ID | 28840 |
| Document Type | Conference paper |
| Collection | DEPARTMENT OF BIOMEDICAL SCIENCES |
| Recommended Citation GB/T 7714 | Gutsaeva, D.,Hussein, K.,Lamoke, F.,et al. Regulation of retinal blood barrier by TNF alpha convertase, ADAM17, and its implication in diabetic macular edema[C], Rockville, MD:The Association for Research in Vision and Ophthalmology, 2016, 3226---. |
| APA | Gutsaeva, D.., Hussein, K.., Lamoke, F.., Kwok, H. F.., Solomon, A.., Martin, P. M.., Al-Shabrawey, M. A.., & Bartoli, M. (2016). Regulation of retinal blood barrier by TNF alpha convertase, ADAM17, and its implication in diabetic macular edema. Investigative Ophthalmology & Visual Science, 3226---. |
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