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Do Gyun Kim, Keun Ho Kim, Kyung Hoon Shin; Effect Of Insulin On Akt, VEGF,HIF-1α on streptozotocin-induced Diabetic rat retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3548.
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Akt is a cytoplasmic serine/threonine kinase and is a key regulator in many cellular processes. VEGF has been identified as a causative factor in retinal neovascularization. HIF(Hypoxia-inducible factor)-1α plays an important role in regulation of hypoxia-responsive genes including VEGF. Also, apoptosis plays a critical role in the pathogenesis of diabetic retinopathy. The incidence of diabetic retinopathy can be reduced when blood glucose is well-controlled. Insulin signaling activates Akt phosphorylation that is known to induce VEGF expression. This cellular signaling and the exact mechanisms of Akt and VEGF in relation to insulin remain poorly understood. In the present study, we investigated the effects of insulin treatment on Akt activation, expressions of VEGF and HIF-1α, and apoptosis in the retina of streptozotocin (STZ)-induced diabetic rats.
Hyperglycemia was induced by the intraperitoneal injection of 50 mg/kg streptozotocin (STZ) to 7 weeks in age male Sprague-Dawley rats weighing 200 ± 10 g. The animals were randomly divided into three groups (n=10 in each group): the control group, the STZ-induced diabetes group, the STZ-induced diabetes and insulin-treated group. We performed morphological analysis through Fundus photograph, Western blot for the expressions of Akt, VEGF, and HIF-1α, and TUNEL staining and caspase-3 immunohistochemistry for apoptosis
Active form of Akt ,Phospho-Akt expression in the retina decreased at 7 weeks after STZ injection in rats. Insulin treatment for 1 week increased p-Akt expression in the retina of diabetic rats. VEGF expression and HIF-1α expression in the retina was enhanced in the STZ-induced diabetic rats and insulin treatment suppressed expression. The numbers of TUNEL-positive and caspase-3-positive cells in the retina were significantly increased in STZ-induced diabetic rats. Insulin treatment significantly suppressed both the STZ-induced increase in DNA fragmentation and caspase-3 expression in the retina
Insulin reduces the activation of caspase-3 through the PI3K/Akt pathway and suppress apoptotic retinal cell death. Increased Akt- phosphorylation by insulin treatment also contributed to the inhibition of retinal apoptosis in the diabetic rats and therefore insulin can alleviate diabetes-induced vascularization by suppressing of VEGF and HIF-1α expressions and by inhibition of apoptotic retinal cell death through up-regulation of Akt expression in the retina
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