Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy
Hyperglycemia results in inhibition of cleavage of integrin-associated protein (IAP) thereby allowing it to bind to SHPS-1 which results in pathophysiologic changes in endothelial function. This study determined if an anti-rat IAP antibody directed against the SHPS-1 binding site which disrupts IAP/...
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| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2019/6456032 |
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| author | Gang Xi Christine Wai David Clemmons |
| author_facet | Gang Xi Christine Wai David Clemmons |
| author_sort | Gang Xi |
| collection | DOAJ |
| description | Hyperglycemia results in inhibition of cleavage of integrin-associated protein (IAP) thereby allowing it to bind to SHPS-1 which results in pathophysiologic changes in endothelial function. This study determined if an anti-rat IAP antibody directed against the SHPS-1 binding site which disrupts IAP/SHPS-1 association could inhibit these pathophysiologic changes. The anti-IAP antibody inhibited IGF-I-stimulated SHPS-1, p52Shc, MAP kinase phosphorylation, and proliferation in endothelial cells. To determine if it could reverse established pathophysiologic changes in vivo, this antibody or normal rat IgG F(ab)2 was injected intraperitoneally for 6 weeks into rats that had diabetes for 4 weeks. Optical coherence tomography (OCT) showed that retinal thickness increased at 4 weeks and this increase was maintained in rats treated with the control antibody for an additional 6 weeks. The increase was reversed by anti-IAP antibody treatment (84.6±2.0 compared to 92.3±2.5 μm, p<0.01). This value was similar to nondiabetic animals (82.2±1.6 μm, p, NS). The anti-IAP antibody also decreased retinal vascular permeability (0.62±0.12 vs. 0.96±0.25%/g/h, p<0.001). To determine if it was effective after local injection, this antibody or control was administered via intravitreal injection. After 3 weeks, retinal thickness increased to 6.4±2.8% in diabetic rats, and IAP antibody treatment prevented this increase (0.8±2.5%, p<0.01). It also prevented the increase of retinal vascular permeability (0.92±0.62 vs. 1.63±0.99%/g/h, p<0.001). Biochemical analyses of retinal extracts showed that the anti-IAP antibody inhibited IAP/SHPS-1 association and SHPS-1 phosphorylation. This resulted in inhibition of AKT activation and VEGF synthesis in the retina: changes associated with increased vascular permeability. We conclude the anti-rat IAP antibody disrupts IAP/SHPS-1 association and attenuates aberrant IGF-I signaling thereby preventing or reversing the progression of retinal pathophysiological changes. |
| format | Article |
| id | doaj-art-44efb40b43564cd7aa0ff0658e8d8189 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-44efb40b43564cd7aa0ff0658e8d81892025-02-03T01:02:02ZengWileyJournal of Diabetes Research2314-67452314-67532019-01-01201910.1155/2019/64560326456032Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic RetinopathyGang Xi0Christine Wai1David Clemmons2Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill NC 27599, USADivision of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill NC 27599, USADivision of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill NC 27599, USAHyperglycemia results in inhibition of cleavage of integrin-associated protein (IAP) thereby allowing it to bind to SHPS-1 which results in pathophysiologic changes in endothelial function. This study determined if an anti-rat IAP antibody directed against the SHPS-1 binding site which disrupts IAP/SHPS-1 association could inhibit these pathophysiologic changes. The anti-IAP antibody inhibited IGF-I-stimulated SHPS-1, p52Shc, MAP kinase phosphorylation, and proliferation in endothelial cells. To determine if it could reverse established pathophysiologic changes in vivo, this antibody or normal rat IgG F(ab)2 was injected intraperitoneally for 6 weeks into rats that had diabetes for 4 weeks. Optical coherence tomography (OCT) showed that retinal thickness increased at 4 weeks and this increase was maintained in rats treated with the control antibody for an additional 6 weeks. The increase was reversed by anti-IAP antibody treatment (84.6±2.0 compared to 92.3±2.5 μm, p<0.01). This value was similar to nondiabetic animals (82.2±1.6 μm, p, NS). The anti-IAP antibody also decreased retinal vascular permeability (0.62±0.12 vs. 0.96±0.25%/g/h, p<0.001). To determine if it was effective after local injection, this antibody or control was administered via intravitreal injection. After 3 weeks, retinal thickness increased to 6.4±2.8% in diabetic rats, and IAP antibody treatment prevented this increase (0.8±2.5%, p<0.01). It also prevented the increase of retinal vascular permeability (0.92±0.62 vs. 1.63±0.99%/g/h, p<0.001). Biochemical analyses of retinal extracts showed that the anti-IAP antibody inhibited IAP/SHPS-1 association and SHPS-1 phosphorylation. This resulted in inhibition of AKT activation and VEGF synthesis in the retina: changes associated with increased vascular permeability. We conclude the anti-rat IAP antibody disrupts IAP/SHPS-1 association and attenuates aberrant IGF-I signaling thereby preventing or reversing the progression of retinal pathophysiological changes.http://dx.doi.org/10.1155/2019/6456032 |
| spellingShingle | Gang Xi Christine Wai David Clemmons Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy Journal of Diabetes Research |
| title | Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy |
| title_full | Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy |
| title_fullStr | Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy |
| title_full_unstemmed | Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy |
| title_short | Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy |
| title_sort | inhibition of aberrant igf i signaling in diabetic male rat retina prevents and reverses changes of diabetic retinopathy |
| url | http://dx.doi.org/10.1155/2019/6456032 |
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