Dataset Information

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

ABSTRACT: Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies.

SUBMITTER: Toh H

PROVIDER: S-EPMC6788790 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Toh Huishi H Smolentsev Alexander A Bozadjian Rachel V RV Keeley Patrick W PW Lockwood Madison D MD Sadjadi Ryan R Clegg Dennis O DO Blodi Barbara A BA Coffey Peter J PJ Reese Benjamin E BE Thomson James A JA

Laboratory investigation; a journal of technical methods and pathology 20190517 10

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlat ...[more]

PMID: 31101854

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Project 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.

Dataset Information

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Publications

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Similar Datasets

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