Ocular Application of the Kinin B.sub.1 Receptor Antagonist LF22-0542 Inhibits Retinal Inflammation and Oxidative Stress in Streptozotocin-Diabetic Rats

• Published in: PloS one 2012-03, Vol.7 (3), p.e33864
• Main Authors: Pouliot, Mylène, Talbot, Sébastien, Sénécal, Jacques, Dotigny, Florence, Vaucher, Elvire, Couture, Réjean
• Format: Article
• Language: English
• Subjects: Diabetic retinopathy; Fluorescein; Inflammation; Mitogens; Oxidative stress; Permeability; RNA; Superoxides; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033864

Kinin B.sub.1 receptor (B.sub.1 R) is upregulated in retina of Streptozotocin (STZ)-diabetic rats and contributes to vasodilation of retinal microvessels and breakdown of the blood-retinal barrier. Systemic treatment with B.sub.1 R antagonists reversed the increased retinal plasma extravasation in STZ rats. The present study aims at determining whether ocular application of a water soluble B.sub.1 R antagonist could reverse diabetes-induced retinal inflammation and oxidative stress. Wistar rats were made diabetic with STZ (65 mg/kg, i.p.) and 7 days later, they received one eye drop application of LF22-0542 (1% in saline) twice a day for a 7 day-period. The impact was determined on retinal vascular permeability (Evans blue exudation), leukostasis (leukocyte infiltration using Fluorescein-isothiocyanate (FITC)-coupled Concanavalin A lectin), retinal mRNA levels (by qRT-PCR) of inflammatory (B.sub.1 R, iNOS, COX-2, ICAM-1, VEGF-A, VEGF receptor type 2, IL-1[beta] and HIF-1[alpha]) and anti-inflammatory (B.sub.2 R, eNOS) markers and retinal level of superoxide anion (dihydroethidium staining). Retinal plasma extravasation, leukostasis and mRNA levels of B.sub.1 R, iNOS, COX-2, VEGF receptor type 2, IL-1[beta] and HIF-1[alpha] were significantly increased in diabetic retinae compared to control rats. All these abnormalities were reversed to control values in diabetic rats treated with LF22-0542. B.sub.1 R antagonist also significantly inhibited the increased production of superoxide anion in diabetic retinae. B.sub.1 R displays a pathological role in the early stage of diabetes by increasing oxidative stress and pro-inflammatory mediators involved in retinal vascular alterations. Hence, topical application of kinin B.sub.1 R antagonist appears a highly promising novel approach for the treatment of diabetic retinopathy.