Ocular application of the kinin B1 receptor antagonist LF22-0542 inhibits retinal inflammation and oxidative stress in streptozotocin-diabetic rats

PLoS One. 2012;7(3):e33864. doi: 10.1371/journal.pone.0033864. Epub 2012 Mar 28.


Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology*
  • Acrylamides / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Bradykinin B1 Receptor Antagonists*
  • Cell Membrane Permeability / drug effects
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy*
  • Fumarates / pharmacology*
  • Fumarates / therapeutic use
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation / drug therapy
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Leukostasis / pathology
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress / drug effects*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Bradykinin B1 / genetics
  • Receptor, Bradykinin B1 / metabolism
  • Retina / drug effects
  • Retina / metabolism
  • Streptozocin
  • Superoxides / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Acrylamides
  • Anti-Inflammatory Agents
  • Bradykinin B1 Receptor Antagonists
  • Fumarates
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1beta
  • N-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)methyl)-2-(2-(((4-methoxy-2,6-dimethylphenyl) sulfonyl)methylamino)ethoxy)-N-methylacetamide, fumarate
  • RNA, Messenger
  • Receptor, Bradykinin B1
  • Superoxides
  • Streptozocin
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Vascular Endothelial Growth Factor Receptor-2