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).
Highlights
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The pro-angiogenic, pro-inflammatory, and vasoactive effects of the kallikrein-kinin system (KKS) make it a promising therapeutic target for treating retinal pathologies associated with inflammation and neovascularization
KKS targeting needs to be carefully documented before clinical application, as this system is involved in physiological functions [4]
Summary
Kinins are small peptides of 9–11 amino acids, including bradykinin (BK), kallidin (KD or Lys-BK), kallidin-like peptide (Arg(1)-kallidin (Arg(0)-bradykinin)), and T-kinin. BK generation in plasma takes part in the intrinsic coagulation pathway activation, involving the interaction of Factor XII (Hageman factor), prekallikrein (PPK), and Factor XI with HK on negatively charged surfaces, such as components of the extracellular matrix or other negatively charged particles (cholesterol sulfate, urate, or phospholipid acid), leading to prothrombotic and inflammatory effects [2,12]. Aminopeptidase P transforms KD and KLP into BK, while kininase I that includes carboxypeptidases N (CPN) and M (CPM) transforms BK, KD, and KLP into des-Arg9-BK, lys-des-Arg9-BK (or des-Arg10-KD), and des-Arg10KLP, respectively. Kininase II ( called angiotensin-1-converting enzyme (ACE)), neutral endopeptidase 24.11 (neprilysin, NEP), and the endothelin-converting enzyme (ECE) degrade BK, KD, and KLP into inactive fragments on the canonical B1 and B2 receptors [4,7,8,9,10,11]. ACE and NEP can metabolize des-Arg9-BK, des-Arg10-KD, and des-Arg10-KLP into inactive metabolites. It is worth noting that the enzymes involved in the catabolism of kinins are involved in the metabolism of other peptides belonging to other systems such as angiotensin, endothelin, anaphylatoxins C3a and C5a, substance P, neurotensin, enkephalins, atrial natriuretic peptides, and chemotactic peptide [5,8,13,14,15,16,17,18,19,20]
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