Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

Abstract

Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (Po0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (Po0.01) and of a-waves for some examined light intensities (Po0.05). Oscillatory potentials were significantly protracted (Po0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome.

Retinal Adaptation to Changing Glycemic Levels in a Rat Model of Type 2 Diabetes

“…From 14 weeks of age, however, the ZDF b/a wave amplitude ratio declined continuously. Pathological changes in the inner retina of patients and other models of diabetes have been extensively documented and the gradual decrease in b-wave responsiveness found here is in accordance with such findings [23], [24], [28], [30], [31]. Retinal vascular perturbations have also been noted in ZDF rats [59]–[61] and there is therefore a possibility that such changes could contribute to the inner retinal changes detected here.…”

“…Most previous ERG studies have found a-wave amplitudes in diabetic rats to be similar or lower than controls [22], [27]–[31]. These seemingly conflicting results could be due to differences in the choice of strain, mode of diabetes induction, duration of diabetes, period of observation, and whether or not low-dose insulin was used to prevent wasting.…”

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

“…The major functional complication in SHR/N-cp rats is renal dysfunction [87], although retinopathy and hearing loss were also observed and studied [156-158]. However, the contribution of hypertension to the pathogenesis of these conditions is complicated by the fact that although these rats were derived from a hypertensive rat strain, at 2 and 3.5 months of age the spontaneous hypertension is found in lean rather than obese male rats [86, 106], but at 8 months of age both lean and obese male rats are hypertensive to the same extent [158].…”

“…However, the contribution of hypertension to the pathogenesis of these conditions is complicated by the fact that although these rats were derived from a hypertensive rat strain, at 2 and 3.5 months of age the spontaneous hypertension is found in lean rather than obese male rats [86, 106], but at 8 months of age both lean and obese male rats are hypertensive to the same extent [158]. Also, renal vascular changes are rare in SHR/N-cp rats [159].…”

“…An early non-proliferative retinopathy is also observed in these rats, resulting from microangiopathy and electroretinographic deficits. But overall, the integrity of the retina is not compromised [158]. Lastly, neuropathy is not described in this strain of animals.…”