Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

• Published in: Diabetologia 2007-09, Vol.50 (9), p.1987-1996
• Main Authors: Zheng, L, Du, Y, Miller, C, Gubitosi-Klug, R. A, Kern, T. S, Ball, S, Berkowitz, B. A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomedical research; Blood vessels; Capillaries - enzymology; Capillary degeneration; Diabetes; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Diabetic retinopathy; Diabetic Retinopathy - enzymology; Dinoprostone - blood; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Histopathology; Hyperglycemia; Inducible nitric oxide synthase; inflammation; Inflammatory diseases; Laboratory animals; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - deficiency; Nitric Oxide Synthase Type II - metabolism; Ophthalmology; PAR activation; Pathogenesis; Physiology; Proteins; Reference Values; Retina; Retina - metabolism; Retinal Degeneration - enzymology; Retinal Vessels - enzymology; Retinopathies; Superoxides - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-007-0734-9

Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos -/-). Materials and methods iNos -/- mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities. Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E₂, superoxide and leucostasis were significantly (p < 0.05) increased in retinas of WT mice diabetic for 2 months compared with non-diabetic WT mice. All of these abnormalities except PAR-modified proteins in retinas were inhibited (p < 0.05) in diabetic iNos -/- mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with non-diabetic WT controls, these increases being significantly inhibited in diabetic iNos -/- mice (p < 0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos -/- mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos -/- mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram. Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.