PURPOSE: We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes. METHODS: To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-α, as data indicate that both proteins are regulated by β-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel β-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-α. RESULTS: Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-α levels. When TNF-α and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-α promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-α) is active. CONCLUSIONS: Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.
PURPOSE: We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes. METHODS: To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-α, as data indicate that both proteins are regulated by β-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel β-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-α. RESULTS: Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-α levels. When TNF-α and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-α promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-α) is active. CONCLUSIONS: Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.
Authors: Jennifer L Kielczewski; Sergio Li Calzi; Lynn C Shaw; Jun Cai; Xiaoping Qi; Qing Ruan; Lin Wu; Li Liu; Ping Hu; Tailoi Chan-Ling; Robert N Mames; Sue Firth; Robert C Baxter; Patric Turowski; Julia V Busik; Michael E Boulton; Maria B Grant Journal: Invest Ophthalmol Vis Sci Date: 2011-10-21 Impact factor: 4.799
Authors: Jennifer L Kielczewski; Ping Hu; Lynn C Shaw; Sergio Li Calzi; Robert N Mames; Tom A Gardiner; Evan McFarland; Tailoi Chan-Ling; Maria B Grant Journal: Am J Pathol Date: 2011-04 Impact factor: 4.307
Authors: Stephen M Cronk; Molly R Kelly-Goss; H Clifton Ray; Thomas A Mendel; Kyle L Hoehn; Anthony C Bruce; Bijan K Dey; Alexander M Guendel; Daniel N Tavakol; Ira M Herman; Shayn M Peirce; Paul A Yates Journal: Stem Cells Transl Med Date: 2015-03-13 Impact factor: 6.940