Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies

Abstract

The kallikrein-kinin system (KKS) contributes to retinal inflammation and neovascularization, notably in diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Bradykinin type 1 (B1R) and type 2 (B2R) receptors are G-protein-coupled receptors that sense and mediate the effects of kinins. While B2R is constitutively expressed and regulates a plethora of physiological processes, B1R is almost undetectable under physiological conditions and contributes to pathological inflammation. Several KKS components (kininogens, tissue and plasma kallikreins, and kinin receptors) are overexpressed in human and animal models of retinal diseases, and their inhibition, particularly B1R, reduces inflammation and pathological neovascularization. In this review, we provide an overview of the KKS with emphasis on kinin receptors in the healthy retina and their detrimental roles in DR and AMD. We highlight the crosstalk between the KKS and the renin–angiotensin system (RAS), which is known to be detrimental in ocular pathologies. Targeting the KKS, particularly the B1R, is a promising therapy in retinal diseases, and B1R may represent an effector of the detrimental effects of RAS (Ang II-AT1R).

Regulations of Retinal Inflammation: Focusing on Müller Glia

“…MG was reported to express ICAM-1, which can be upregulated in response to CD40, a member of the TNF superfamily that activates NFκB signaling pathway, indicating its role as a mediator in retinal inflammatory response ( Portillo et al, 2014 ). The kallikrein-kinin system (KKS) plays important roles in neovascularization and retinal inflammation ( Othman et al, 2021 ). Activated MG express kinin B 1 receptor, which can be induced by activation of NF-κB and the subsequent release of pro-inflammatory cytokines and is detrimental to the retina ( Couture et al, 2014 ; Hachana et al, 2018 ).…”

Editorial: Kinin 2022 Meeting, Annecy, France

“…Elvire Vaucher from the University of Montreal showed that BK is a potential therapeutic target in age-related macular degeneration (AMD) [10]. Both anti-VEGF and B1R antagonism reduced AMD.…”

Molecules related to diabetic retinopathy in the vitreous and involved pathways

“…KKS is composed of two independently regulated proteolytic pathways mediated by tissue kallikrein (TK) and plasma kallikrein (PK) in human, both of which are expressed in eye and found to be related to the progression of DR via the production of bradykinin and spontaneous stimulation of bradykinin receptors [10] . After the activation of BK receptors, KKS performs a variety of physiological effects such as coagulation, fibrinolysis, angiogenesis, etc [10] . Up to now, there have been a few studies on the role of KKS in the vitreous of DR patients.…”