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Rahmeh Othman, Elvire Vaucher, Réjean Couture; The role of inducible nitric oxide synthase in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1210. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Overexpression of inducible nitric oxide synthase (iNOS) has been reported in diabetic retinopathy (DR). The activation of iNOS produces large amounts of nitric oxide, which can react with superoxide anion to form peroxynitrite, a highly toxic molecule that causes damage to proteins, lipids and DNA. However, the role of iNOS in DR remains elusive. Thus, the aim of this study was to investigate the role of iNOS in a rat model of DR.
Diabetes was induced in male Wistar rats (200-230 g) by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg b.w.). One week later, rats were randomly divided into four groups (N=5) and treated for one week as follows: Gr 1: control rats, Gr 2: control rats treated with the selective iNOS inhibitor (1400W, 0.06 μM, twice a day by eye-drops x 7 days), Gr 3: STZ-diabetic rats, Gr 4: STZ-diabetic rats + 1400W. At the end of treatment and two weeks post-STZ, three series of experiments were carried out to measure retinal vascular permeability (by Evans blue dye method) and the expression of vasoactive and inflammatory mediators, including iNOS, VEGF-A, VEGF-R2, IL-1β, Cox-2, TNF-α, bradykinin 1 and 2 receptors and carboxypeptidase M/kininase 1 (by Western Blotting and qRT-PCR). The oxidative stress (nitrosylation of proteins) was also assessed by Western Blotting. One-way Anova with Bonferroni test was used for statistical analysis.
STZ-diabetic rats showed a significant increase in retinal vascular permeability (22.8 μg Evans blue dye/g of fresh retinas, p=0.016) compared with control and control treated rats (17.2 μg/g and 16.8 μg/g, respectively). The 1400W treatment decreased significantly the retinal vascular permeability in treated STZ-diabetic rats compared with non treated STZ-diabetic rats (17.4 μg/g, p=0.016). The expression of all vasoactive and inflammatory markers and protein’s nitrosylation were also significantly increased in retinas of STZ-diabetic rats compared with control retinas. The one-week treatment with 1400W reversed to control levels all these responses in STZ-diabetic retinas.
Data suggest that iNOS plays a critical role in the early stage of DR by increasing the oxidative stress (peroxynitrite) and inflammation through a mechanism involving kinin receptors, VEGF and the cytokine pathway. Hence, its inhibition by ocular application of 1400W may represent a promising and non-invasive therapeutic approach in the treatment of DR.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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