title: Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes.
abstract: OBJECTIVE
  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 (-/-)).
  
  
  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 E(2), 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
  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.
authors.affiliation: Department of Medicine, 448B Biomedical Research Building, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. ling.zheng@case.edu.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Medicine, 448B Biomedical Research Building, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Medicine, 448B Biomedical Research Building, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.|Alcon Research, Fort Worth, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Gubitosi-Klug
authors.affiliation: Department of Medicine, 448B Biomedical Research Building, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. tsk@case.edu.|Department of Ophthalmology, 434 Biomedical Research Building, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. tsk@case.edu.|Cleveland VAMC Research Service 151, Cleveland, OH, USA. tsk@case.edu.
authors.forename: T S
authors.initials: TS
authors.lastname: Kern
authors.affiliation: Cleveland VAMC Research Service 151, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ball
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI, USA.|Department of Ophthalmology, Wayne State University, Detroit, MI, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Berkowitz
mesh_terms: D000818:Animals; D002196:Capillaries / Q000201:enzymology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000201:enzymology*; D015232:Dinoprostone / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism*; D012016:Reference Values; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000201:enzymology*; D012171:Retinal Vessels / Q000201:enzymology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D015232:Dinoprostone