Inhibition of Aberrant IGF-I Signaling in Diabetic Male Rat Retina Prevents and Reverses Changes of Diabetic Retinopathy. (27th March 2019)

• Record Type: Journal Article
• Authors: Xi, Gang; Wai, Christine; Clemmons, David
• Other Names: Kakehashi Akihiro Academic Editor.
• Is Part Of: Journal of diabetes research. Volume 2019(2019)
• Publication Date: 2019-03-27
• Subjects: Diabetes -- Periodicals; Diabetes -- Pathophysiology -- Periodicals; Diabetes -- Prevention -- Periodicals; Diabetes -- Etiology -- Periodicals; Diabetes -- Epidemiology -- Periodicals; Diabetes -- Pathogenesis -- Periodicals; 616.462005
• DOI: 10.1155/2019/6456032
• Languages: English
• ISSNs: 2314-6745

Abstract

Abstract : 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 to92.3 ± 2.5 μ m, p < 0.01 ). This value was similar to nondiabetic animals (82.2 ± 1.6 μ m, 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 to6.4 ± 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.