Nadine Reichhart1, Sergio Crespo-Garcia2, Nadine Haase3,4,5, Michaela Golic3,5,6,7, Sergej Skosyrski2, Anne Rübsam2,8, Christina Herrspiegel2, Norbert Kociok2, Natalia Alenina4,9, Michael Bader4,5,9,10,11, Ralf Dechend3,5,11,12, Olaf Strauss2, Antonia M Joussen13. 1. Department of Ophthalmology, Charité-Universitätsmedizin Berlin Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. nadine.reichhart@charite.de. 2. Department of Ophthalmology, Charité-Universitätsmedizin Berlin Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. 3. Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité-Universitätsmedizin Berlin, Berlin, Germany. 4. Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 5. Berlin Institute of Health, Berlin, Germany. 6. Department of Obstetrics, Charité-Universitätsmedizin Berlin Campus Virchow Klinikum, Berlin, Germany. 7. Department of Gynecology, Charité-Universitätsmedizin Berlin Campus Virchow Klinikum, Berlin, Germany. 8. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA. 9. German Center for Cardiovascular Disease, Berlin, Germany. 10. Department of Biology, Universität zu Lübeck, Lübeck, Germany. 11. Charité-Universitätsmedizin Berlin Campus Berlin-Buch, Berlin, Germany. 12. Department of Cardiology and Nephrology, HELIOS Klinikum Berlin-Buch, Berlin, Germany. 13. Department of Ophthalmology, Charité-Universitätsmedizin Berlin Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. antonia.joussen@charite.de.
Abstract
AIMS/HYPOTHESIS: Although the renin-angiotensin system plays an important role in the progression of diabetic retinopathy, its influence therein has not been systematically evaluated. Here we test the suitability of a new translational model of diabetic retinopathy, the TetO rat, for addressing the role of angiotensin-II receptor 1 (AT1) blockade in experimental diabetic retinopathy. METHODS: Diabetes was induced by tetracycline-inducible small hairpin RNA (shRNA) knockdown of the insulin receptor in rats, generating TetO rats. Systemic treatment consisted of an AT1 blocker (ARB) at the onset of diabetes, following which, 4-5 weeks later the retina was analysed in vivo and ex vivo. Retinal function was assessed by Ganzfeld electroretinography (ERG). RESULTS: Retinal vessels in TetO rats showed differences in vessel calibre, together with gliosis. The total number and the proportion of activated mononuclear phagocytes was increased. TetO rats presented with loss of retinal ganglion cells (RGC) and ERG indicated photoreceptor malfunction. Both the inner and outer blood-retina barriers were affected. The ARB treated group showed reduced gliosis and an overall amelioration of retinal function, alongside RGC recovery, whilst no statistically significant differences in vascular and inflammatory features were detected. CONCLUSIONS/ INTERPRETATION: The TetO rat represents a promising translational model for the early neurovascular changes associated with type 2 diabetic retinopathy. ARB treatment had an effect on the neuronal component of the retina but not on the vasculature.
AIMS/HYPOTHESIS: Although the renin-angiotensin system plays an important role in the progression of diabetic retinopathy, its influence therein has not been systematically evaluated. Here we test the suitability of a new translational model of diabetic retinopathy, the TetO rat, for addressing the role of angiotensin-II receptor 1 (AT1) blockade in experimental diabetic retinopathy. METHODS:Diabetes was induced by tetracycline-inducible small hairpin RNA (shRNA) knockdown of the insulin receptor in rats, generating TetO rats. Systemic treatment consisted of an AT1 blocker (ARB) at the onset of diabetes, following which, 4-5 weeks later the retina was analysed in vivo and ex vivo. Retinal function was assessed by Ganzfeld electroretinography (ERG). RESULTS: Retinal vessels in TetO rats showed differences in vessel calibre, together with gliosis. The total number and the proportion of activated mononuclear phagocytes was increased. TetO rats presented with loss of retinal ganglion cells (RGC) and ERG indicated photoreceptor malfunction. Both the inner and outer blood-retina barriers were affected. The ARB treated group showed reduced gliosis and an overall amelioration of retinal function, alongside RGC recovery, whilst no statistically significant differences in vascular and inflammatory features were detected. CONCLUSIONS/ INTERPRETATION: The TetO rat represents a promising translational model for the early neurovascular changes associated with type 2 diabetic retinopathy. ARB treatment had an effect on the neuronal component of the retina but not on the vasculature.
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