title: Ocular application of the kinin B1 receptor antagonist LF22-0542 inhibits retinal inflammation and oxidative stress in streptozotocin-diabetic rats.
abstract: OBJECTIVE
  Kinin B(1) receptor (B(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(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(1)R antagonist could reverse diabetes-induced retinal inflammation and oxidative stress.
  
  
  METHODS
  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(1)R, iNOS, COX-2, ICAM-1, VEGF-A, VEGF receptor type 2, IL-1β and HIF-1α) and anti-inflammatory (B(2)R, eNOS) markers and retinal level of superoxide anion (dihydroethidium staining).
  
  
  RESULTS
  Retinal plasma extravasation, leukostasis and mRNA levels of B(1)R, iNOS, COX-2, VEGF receptor type 2, IL-1β and HIF-1α 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(1)R antagonist also significantly inhibited the increased production of superoxide anion in diabetic retinae.
  
  
  CONCLUSIONS
  B(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(1)R antagonist appears a highly promising novel approach for the treatment of diabetic retinopathy.
authors.affiliation: École d'optométrie, Université de Montréal, Montréal, Canada.
authors.forename: Mylène
authors.initials: M
authors.lastname: Pouliot
authors.forename: Sébastien
authors.initials: S
authors.lastname: Talbot
authors.forename: Jacques
authors.initials: J
authors.lastname: Sénécal
authors.forename: Florence
authors.initials: F
authors.lastname: Dotigny
authors.forename: Elvire
authors.initials: E
authors.lastname: Vaucher
authors.forename: Réjean
authors.initials: R
authors.lastname: Couture
mesh_terms: D000178:Acrylamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065169:Bradykinin B1 Receptor Antagonists; D002463:Cell Membrane Permeability / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D018921:Leukostasis / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D013311:Streptozocin; D013481:Superoxides / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000178:Acrylamides; D000893:Anti-Inflammatory Agents; D065169:Bradykinin B1 Receptor Antagonists; D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; C512396:N-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)methyl)-2-(2-(((4-methoxy-2,6-dimethylphenyl) sulfonyl)methylamino)ethoxy)-N-methylacetamide, fumarate; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D013481:Superoxides; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D040301:Vascular Endothelial Growth Factor Receptor-2