Altered expression of aquaporins 1 and 4 coincides with neurodegenerative events in retinas of spontaneously diabetic Torii rats

Abstract

Evidence is mounting that not only microangiopathy, but also neurodegenerative events occur in the retinas of humans and rodents with early diabetes. Diverse pathologies are known to alter the amount and/or location of glial expression of the water-selective channels aquaporins (AQPs) 1 and 4. However, the temporal relationships among glial activation, the altered expression of the AQP proteins and neuronal death in the retinas of diabetic animals remains to be investigated. Male spontaneously diabetic Torii (SDT) rats reportedly develop diabetes by 40 weeks of age at the latest and manifest proliferative diabetic retinopathy at 50 weeks or later. This study compared temporal changes in neuroretinal apoptosis, glial fibrillary acidic protein (GFAP) expression and the expression of AQPs 1 and 4 between SDT rat retinas and age-matched Sprague-Dawley (SD) rat retinas. Cell death was detected by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling on retinal flatmounts and activated caspase 3 immunofluorescence of retinal cryosections. The expression of GFAP and AQPs 1 and 4 was assessed by immunohistochemistry of cryosections and retinal flatmounts. Diabetes started to develop around 15 weeks in SDT rats. Apoptotic cells in the ganglion cell layer and the inner nuclear layer were significantly more numerous in 40-week-old SDT rat retinas than in either age-matched SD rat retinas or 10-week-old SDT rats. GFAP immunoreactivity was confined to the nerve fiber layer both in SD and SDT rats at 10 weeks, whereas it spanned the whole retina in SDT rats, but not in SD rats, at 40 weeks. AQP1 was expressed in the outer retina, whereas AQP4 was expressed in the perivascular and end feet of Müller cells and astrocytes in the inner retina in the control SD rats and the SDT rats at 10 weeks. The perivascular AQPs shifted from AQP4 to AQP1 in 40-week-old SDT rats that exhibited marked hyperglycemia. Thus, the development of diabetes increases neuroretinal apoptosis, and this coincides with an altered expression pattern of GFAP and water-selective channels AQPs 1 and 4 in SDT rats.

Characterisation of the vitreous proteome in proliferative diabetic retinopathy

“…Recent advances in proteome analysis methods have allowed the further exploration and acquisition of vitreous protein profiles [1,6-8]. In the last few years, proteomics has been applied to explore proteins which were differentially expressed in patients with proliferative diabetic retinopathy and in nondiabetic patients [9-14]. Previous studies have identified some proteins that are differentially expressed in the vitreous of PDR patients.…”

Localisation of Aquaporin-1 In Diabetic Rat Retina and Ciliary Body

“…farelerde oluşturdukları prematüre retinopati modelinde, AQ1 proteininin dış retinada, özellikle rod ve koni tabakalarında lokalize olduğunu bulmuşlardır. Fukuda ve ark [9] AQP1 ve AQP4'ün diabetik Torii sıçanların iç ve dış retinalarında farklı şekillerde lokalizasyonlarını göstermişlerdir. Bizim çalışmamız da bu bulguları destekler şekilde AQP1'nin diabetik sıçanlardaki artmış ifadesini göstermiştir, Fakat çalış-mamızda AQP1'in immunoreaktivitesinde fark görülmesine rağ-men, diabetik ve diabetik olmayan sıçan retina ve siliyer cisim morfolojilerinde anlamlı bir fark bulunamamıştır.…”

Animal Models of Diabetic Retinopathy

“…Boxes represent the point in the pathway targeted by animal models. Italicized text corresponds to the induced models and bold text corresponds to the genetic models [ 20,[145][146][147][148] SDT QTL Gisdt1, 2, 3 [149][150][151][152][153][154][155] develop proliferative retinopathy [50]. Monkeys thus appear to be surprisingly resilient to induction of DR despite removal of the pancreas, long-term diabetes, and poor control of blood sugar levels.…”

“…SDT rats are characterized by retinal dysfunction, which includes retinal detachment with fibrous proliferation, absence of retinal ischemia in the presence of neovascularization, leukostasis, increased number of apoptotic cells in the GCL and INL, vascular lesions, and pericyte loss [151][152][153][154]. A distinct feature of this model is the appearance of large retinal folds with extensive leakage around the optic disc, similar to retinal detachment observed in humans [151][152][153][154]. The SDT rat is the rat model that most closely resembles the pathophysiology seen in humans; however, the absence of microaneurysm makes them a more suitable model for studying NPDR.…”