Targeting the kallikrein-kinin system as a new therapeutic approach to diabetic retinopathy.
Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus that can lead to visual impairment and blindness. There is no approved pharmacological treatment for DR; however, laser therapy, steroids and anti-VEGF agents appear to provide some benefit. Hyperglycemia, advanced glycation end products, growth factors, and elevated levels of circulating and vitreous cytokines and chemokines can all trigger an inflammatory response of the retinal vasculature. Features of DR can include diabetic macular edema, microhemorrhage, loss of capillaries, development of avascular areas and the vitreo-retinal proliferation of neovessels. The kallikrein-kinin system (KKS) has long been recognized as a key player of inflammatory processes in various organs. Intravitreally administered recombinant plasma kallikrein has been demonstrated to produce retinal vascular leakage and hemorrhage, while both kinin B1 and B2 receptor agonists have induced retinal edema. Furthermore, kallikrein inhibitors and peptide-based B1 receptor antagonists could reduce or block retinal vascular permeability in diabetic rats. In a diabetic rat model, FOV-2304 (Fovea Pharmaceuticals SA), a non-peptide selective B1 receptor antagonist, consistently blocked retinal vascular permeability, inhibited leukocyte adhesion and abolished the retinal mRNA expression of several inflammatory mediators. Although additional studies are required to investigate the role of the KKS in early capillary loss and late-stage neovascularization processes, the blockade of the KKS is a promising therapeutic strategy for DR.
Pruneau
Didier
D
Fovea Pharmaceuticals SA, Vision Institute, 17 Rue Moreau, 75012 Paris, France. pruneau@fovea-pharma.com
Bélichard
Pierre
P
Sahel
José-Alain
JA
Combal
Jean-Philippe
JP
D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015195:Drug Design; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D016234:Kallikrein-Kinin System / Q000187:drug effects* / Q000276:immunology; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D051381:Rats; D012171:Retinal Vessels / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D065169:Bradykinin B1 Receptor Antagonists; D007610:Kallikreins