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Andreas Ohlmann, Ludwig F. Zeilbeck, Thomas Langmann, Ernst R. Tamm; Norrin Mediates Its Protective Properties Against Oxygen-induced Retinal Damage By Induction Of IGF-1 Expression. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3982.
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To analyze if norrin, a secreted protein that controls capillary formation in the developing retina and protects from vascular damage after oxygen-induced retinopathy (OIR) via the Wnt/(beta)-catenin pathway, mediates its function, at least partially, by induction of insulin-like growth factor (IGF)-1.
Human dermal microvascular endothelial cells (HDMEC) and rat Mueller cells were incubated with Norrin and/or Dickkopf (DKK)-1, an inhibitor of the canonical Wnt/(beta)-catenin signaling pathway. The expression of IGF-1 was analyzed by quantitative real-time RT-PCR and western blotting. In parallel experiments, transgenic mice with an ocular overexpression of Norrin ((beta)B1-Norrin; Ohlmann et al., J. Neurosci. 2005, 2010) were investigated for retinal IGF-1 mRNA expression during retinal development and after induction of OIR following incubation with 75% oxygen from postnatal day (P) 7 to P12. In addition, an inhibitory anti-IGF-1 antibody was injected into the vitreous body of oxygen-treated mice at P12 and sizes of vasoobliterated areas were measured at P14.
In both HDMEC and Mueller cells that had been treated with 20 ng/ml Norrin, a significant induction of IGF-1 mRNA was detected when compared to untreated controls. When higher concentrations were used, IGF-1 expression was less prominent, indicating dose dependency of Norrin treatment. Comparable results were observed regarding the amounts of IGF-1 synthesized in HDMEC or Mueller cells. After an additional treatment of the cells with DKK-1, the Norrin-mediated effects on IGF-1 expression were blocked almost completely.During development of the eye, only minor changes in IGF-1 mRNA expression were detected in retinae from (beta)B1-Norrin mice when compared to wild type littermates. However, after induction of OIR, IGF-1 mRNA levels increased substantially in transgenic mice at P13. In oxygen-treated transgenic mice with an injection of inhibitory anti-IGF-1 antibodies into the vitreous cavity at P12, a significant increase in vasoobliterated retinal areas was observed at P14.
Norrin induces the expression of IGF-1 via an activation of the classical Wnt/(beta)-catenin pathway in vitro and in vivo. The protective effects of Norrin against OIR are mediated, at least partially, via the induction of IGF-1.
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