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).

Keywords: age-related macular degeneration; diabetic retinopathy; kallikrein-kinin system; kinin receptors.

Figure 1

Biosynthesis and metabolism of kinins. Low- and high-molecular-weight kininogens are cleaved by tissue kallikrein and plasma kallikrein, respectively, into kallidin (in humans) and kallidin-like peptide (in rodents) [5,6], and bradykinin. Bradykinin, kallidin, and kallidin-like peptide are then either converted by the action of kininase I to des-Arg⁹-bradykinin, des-Arg¹⁰-kallidin, and des-Arg¹⁰-kallidin-like peptide, respectively, or inactivated by kininase II, neutral endopeptidase 24.11 (neprilysin, NEP), and the endothelin-converting enzyme [4,7,8,9,10,11]. ACE, angiotensin-1- converting enzyme (also known as kininase II); APP, aminopeptidase P; B1R, bradykinin type 1 receptor; B2R, bradykinin type 2 receptor; BK, bradykinin; ECE, endothelin-converting enzyme; KD, kallidin; KLP, kallidin-like peptide, which is Arg(1)-kallidin (Arg(0)-bradykinin); NEP, neutral endopeptidase; PK, plasma kallikrein; TK, tissue kallikrein.

Figure 2

kallikrein-kinin system in diabetic retinopathy. Schematic proposal of the signaling pathways activated by B1R and B2R in diabetic retinopathy. PGs, prostaglandins; PGI2, prostacyclin; PLA2, phospholipase A2; Src, kinase proto-oncogene tyrosine-protein kinase; VEC, vascular endothelial cadherin; VEC-P, phosphorylated vascular endothelial cadherin. The human eye anatomy diagram was acquired from Shutterstock (http://www.shutterstock.com, accessed on 16 July 2021).

Figure 3

Transcriptomic impact of age-related macular degeneration on the kallikrein-kinin system in human choroid tissues by single-cell RNA seq. (a) Dimensionality reduction and cluster visualization with UMAP plot. Color-coded clusters represent the different choroid cell types (see legend in bottom right corner) identified by single-cell RNAseq analysis of post-mortem control (left panel) and neovascular AMD (right panel) choroids (public data deposited on GEO with reference number GSE135922). (b) Dotplot of the expression of the gene markers used to identify choroid cell types. (c) Dotplot of the expression of the genes involved in the KSS pathway across choroidal cell types from control (black legend) and neovascular (nv)-AMD (red legend) samples. As shown in (a–c), KLKB1, BDKRB1, and BDKRB2 are mainly expressed in choroidal endothelial cells, albeit at low expression levels; some expression was also detected in fibroblasts. (d) Dimensionality reduction and cluster visualization with UMAP plot of the subpopulations of choroid endothelial cells of post-mortem control (left panel) and neovascular AMD (right panel) choroids. Choroid cells clustered into four distinct endothelial cell subtypes: two venous subtypes, one choriocapillaris subtype, and one arterial subtype (see legend on right side). (e) Dotplot of the expression of the specific gene markers in these endothelial subcluster, as annotated by Voigt et al., [150]. (f) Visualization with UMAP plot of E SELECTIN (SELE) and VCAM1 expression co-localizing to vein 2 subcluster, a signature reminiscent of post-capillary venous identity. (g) Dotplot of the expression of genes involved in the KSS pathway across choroidal endothelial cell subtypes from control (black legend) and neovascular (nv)-AMD (red legend) samples. Vein cluster 2 showed greater expression of KKS genes, notably BDKRB1, BDKRB2, and MME, across all choroidal endothelial cells of control and nv-AMD choroid samples. In all the dotplots, the size of the dots encodes the percentage of cells within a class, and the color scale encodes the average expression level across all cells within a class (red being the strongest value). Av. Exp., average gene expression across all cells within each cluster; % Exp., percentage of cells with detectable gene expression within each cluster.

Figure 4

Crosstalk between the kallikrein-kinin system (KKS) and the renin–angiotensin system (RAS). ACE, angiotensin -1 -converting enzyme (kininase II); ACE2, angiotensin-converting enzyme 2; Ang I, angiotensin I; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; BK, bradykinin; MasR, Mas receptor; NEP, neutral endopeptidase 24.11 (neprilysin, NEP).