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R.S. Singh, P.E. Fort, C.E. N. Reiter, M.B. Grant, D. Accili, C.R. Kahn, S.K. Bronson, T.W. Gardner, Penn State Retina Research Group; Impairment Of The Retinal Insulin Receptor: Implications For Retinal Neurodegenerations . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4230.
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The normal retinal insulin receptor (IR) exhibits high constitutive kinase activity that is reduced in diabetes. Systemic insulin therapy reduces retinal cell death in diabetic rats, and insulin has pro–survival effects on retinal neurons in culture. Therefore, we applied genetic and gene–knockdown methods to investigate the function of the retinal IR.
Retinas from 3 animal models of insulin receptor depletion were studied for alterations in IR signaling and evidence of retinal dysfunction using biochemical and histochemical methods. First, selective knockdown of the IR was achieved in normal rat eyes by intravitreal injection of a vector with a hammerhead ribozyme directed against the IR mRNA. Second, IR deficient mice with tissue–specific expression of the human IR transgene driven by the transthyretin (TTR) promoter exhibiting euglycemia and no detectable retinal IR expresseion were analyzed. Third, IR signaling and retinal phenotype were evaluated in IR heterozygous mice (IR +/–) expressing only one copy of the IR gene.
All 3 models have shown a dramatic reduction of IR content in the retina; the reduction is dose– and time–dependent in the ribozyme model. Immunohistochemical analysis showed no IR expression, and significantly decreased intensity on retinal sections, respectively, from TTR–IR mice and IR (+/–) animals. Selective IR expression impairment also reduced IRS–2 and Akt3 contents, while the content of IGF–1 receptor and IRS–1 did not decrease. Astrocyte glial fibrillary acidic protein was reduced by IR knock–down.
Animal models with selective IR depletion provide important tools to understand the physiological role of retinal insulin signaling during development and retinal degenerations such as diabetic retinopathy.
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