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L. Zheng, Y. Du, C. Miller, R. Gubitosi–Klug, B.A. Berkowitz, T.S. Kern; Critical Role of iNOS in Pathogenesis of Early Stages of Diabetic Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1712.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes results in upregulation of a number of components of the inflammatory response in the retina, including nitric oxide (NO) and inducible nitric oxide synthase (iNOS). We have now used mice who are deficient in iNOS (iNOS–/–) to investigate the role of this inflammatory enzyme in the pathogenesis of the early stages of diabetic retinopathy.
iNOS–/– mice and wildtype C57Bl/6 (iNOS+/+) mice made diabetic with STZ or kept as nondiabetic controls were sacrificed at 24 weeks and 36 weeks of diabetes for assessment of vascular histopathology, at 14 weeks for quantitation of ganglion cell loss, and at 8–10 weeks for assessment of biochemical and physiological abnormalities. Severity of hyperglycemia was not different between diabetic iNOS–/– and iNOS+/+ animals.
The concentration of NO and nitration of proteins was increased in retinas of diabetic wildtype animals, and both of these abnormalities were inhibited (P < 0.05) in iNOS–/– diabetic animals. As expected, the number of acellular capillaries was significantly (P <0.01) increased in retinas from wildtype mice diabetic for 36 weeks (but not 24 weeks) compared to age–matched nondiabetic wildtypes. This increase was significantly (P <0.05) inhibited in diabetic iNOS–/– mice. Retinas from iNOS+/+ wildtype mice diabetic for 14 weeks were significantly thinner than their nondiabetic controls (due to changes in thickness of inner and outer retinal plexiform layers), and iNOS–/– mice did not show evidence of these changes. We found no evidence of ganglion cell loss in either diabetic wildtype or iNOS–/– mice. Retinas from diabetic wildtype mice produced significantly (P <0.05) more PGE2 and superoxide, and caused more leukocyte adherence in the retinal vasculature than did samples from wildtype nondiabetics. Each of these abnormalities was significantly inhibited in iNOS–/– mice.
The present studies demonstrate that iNOS plays an important role in the pathogenesis of the early stages of diabetic retinopathy. These results provides further support for the postulate that diabetic retinopathy develops via an inflammatory–like process.
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