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V Poulaki, AM Joussen, N Mitsiades, AP Adamis; The Role of IGF-I in the Pathogenesis of Diabetic Retinopathy . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2966.
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Purpose: Although IGF-I has been associated with diabetic retinopathy, proof of a direct relationship has been lacking. The role of IGF-I was investigated in a relevant animal model of diabetic retinopathy. Methods: Long Evans rats received intraperitoneal injections of the NF-kB inhibitor SN50 or vehicle, and 2 hrs later an intravitreous injection of the recombinant IGF-I in one eye and PBS in the contralateral eye. Streptozotocin-induced diabetic rats were implanted with osmotic pumps containing PI-3 kinase, Akt kinase, or NF-kB inhibitors, or a neutralizing antibody against IGF-I, and were sacrificed 7 days later. Vascular leakage was evaluated with the Evans Blue method, leukocyte adhesion with FITC-conjugated lectin, and retinal protein levels for VEGF, IGF-I and IGF-BP3 were measured via ELISA. HIF-1a levels were estimated via Western Blotting and Akt kinase activity via a previously described quantitative assay. Results: Intravitreous injection of IGF-I increased retinal levels for HIF-1a and VEGF. The IGF-1-induced vascular leakage was reduced via NF-kB inhibition. IGF-I, IGF-BP3 and HIF-1a protein levels were increased in the early diabetic rat retina, and coincided with the increases in VEGF levels. Systemic inhibition of IGF-1 reduced retinal Akt kinase activity, HIF-1a, VEGF and ICAM-1 levels, retinal leakage, and leukostasis. PI3 kinase and Akt kinase inhibitors had the same effects without altering IGF-I levels. The inhibition of NF-kB suppressed VEGF levels to a lesser degree without altering HIF-1a levels. Conclusion: In early diabetes, endogenous IGF-I induces retinal VEGF, ICAM-1 leukocyte adhesion and subsequently vascular leakage through two pathways: one involving PI-3K/Akt-mediated activation of HIF-1a and a second utilizing NF-kB.
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