Characterization of a Mouse Model of Hyperglycemia and Retinal Neovascularization

Abstract

One of the limitations of research into diabetic retinopathy is the lack of suitable animal models. To study how the two important factors-hyperglycemia and vascular endothelial growth factor-interact in diabetic retinopathy, the Akimba mouse (Ins2 ). C57Bl/6 and the parental and Akimba mouse lines were characterized by biometric measurements, histology, immunohistochemistry, and Spectralis Heidelberg retinal angiography and optical coherence tomography. The Akimba line not only retained the characteristics of the parental strains, such as developing hyperglycemia and retinal neovascularization, but developed higher blood glucose levels at a younger age and had worse kidney-body weight ratios than the Akita line. With aging, the Akimba line demonstrated enhanced photoreceptor cell loss, thinning of the retina, and more severe retinal vascular pathology, including more severe capillary nonperfusion, vessel constriction, beading, neovascularization, fibroses, and edema, compared with the Kimba line. The vascular changes were associated with major histocompatibility complex class II ؉ cellular staining throughout the retina. Together, these observations suggest that hyperglycemia resulted in higher prevalences of edema and exacerbated the vascular endothelial growth factordriven neovascular and retinal changes in the Akimba line. Thus, the Akimba line could become a useful model for studying the interplay between hyperglycemia and vascular endothelial growth factor and for testing treatment strategies for potentially blinding complications, such as edema.

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

“…For this reason, the research group of Prof. Racokzy recently generated the Akimba (Ins2 Akita VEGF +/-) mouse model by crossing the diabetic Akita mouse line (Ins2 Akita ) with the Kimba mouse line (VEGF +/-) [119]. The Akita mouse is a naturally occurring insulin-dependent type 1 diabetes model [120,121].…”

“…The heterozygous Akita male mice develop features similar to early pathophysiological changes of diabetic complications, but fail to exhibit the advanced stage vascular dysfunctions. The non-diabetic Kimba (trVEGF029) mouse model, in which photoreceptors transiently overexpress hVEGF, is characterized by several early and advanced DR-associated vascular changes such as vascular permeability, capillary non-perfusion, microaneurysms and retinal neovascularization [119,[122][123][124][125][126][127]. It has been reported that the combination of high blood glucose levels and VEGF overexpression exacerbates the vascular complications in the Akimba mouse eye [119,127].…”

Animal Models of Diabetic Retinopathy

“…By P28, microvascular abnormalities and capillary dropout are observed and continue until 9 weeks of age, at which time pericyte loss is detected [123,124]. The Akimba mice are hyperglycemic and appear to have additive effects from both parental strains [125,126]. Akimba mice are characterized by pericyte and vessel loss and retinal neovascularization with diffuse vascular leakage that is observed in latestage DR [125,127].…”

“…Akimba mice are characterized by pericyte and vessel loss and retinal neovascularization with diffuse vascular leakage that is observed in latestage DR [125,127]. Additionally, the Akimba mouse exhibits leaky capillaries, tortuous vessels, and microaneurysm by 8 weeks [125]. Enhanced photoreceptor loss, reduction of retina thickness, increased persistence of edema, and retinal detachment are observed as the animal ages and disease progresses [125].…”

“…The Akimba mice are hyperglycemic and appear to have additive effects from both parental strains [125,126]. Akimba mice are characterized by pericyte and vessel loss and retinal neovascularization with diffuse vascular leakage that is observed in latestage DR [125,127]. Additionally, the Akimba mouse exhibits leaky capillaries, tortuous vessels, and microaneurysm by 8 weeks [125].…”