Differential Expression of Kinin Receptors in Human Wet and Dry Age-Related Macular Degeneration Retinae

Abstract

Kinins are vasoactive peptides and mediators of inflammation, which signal through two G protein-coupled receptors, B1 and B2 receptors (B1R, B2R). Recent pre-clinical findings suggest a primary role for B1R in a rat model of wet age-related macular degeneration (AMD). The aim of the present study was to investigate whether kinin receptors are differentially expressed in human wet and dry AMD retinae. The cellular distribution of B1R and B2R was examined by immunofluorescence and in situ hybridization in post-mortem human AMD retinae. The association of B1R with inflammatory proteins (inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor A (VEGFA)), fibrosis markers and glial cells was also studied. While B2R mRNA and protein expression was not affected by AMD, a significant increase of B1R mRNA and immunoreactivity was measured in wet AMD retinae when compared to control and dry AMD retinae. B1R was expressed by Müller cells, astrocytes, microglia and endothelial/vascular smooth muscle cells, and colocalized with iNOS and fibrosis markers, but not with VEGFA. In conclusion, the induction and upregulation of the pro-inflammatory and pro-fibrotic kinin B1R in human wet AMD retinae support previous pre-clinical studies and provide a clinical proof-of-concept that B1R represents an attractive therapeutic target worth exploring in this retinal disease.

Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies

“…Consistently with the roles of kinin receptors in both inflammation and neovascularization, we showed that most upregulated inflammatory mediators were blocked by B1R inhibition in DR and AMD [58][59][60]. B1R was shown to be expressed on Müller cells and astrocytes in these retinal pathologies in rat and post-mortem human retina [58,59,93], and on microglia in post-mortem human wet AMD retina [93]. Macroglia play a primary role in vascular function and neuronal integrity of the retina [145].…”

“…In a mice model of CNV, B2R blockade with Icatibant had a limited effect, yet concomitant inhibition of B2R and kininase II had additive suppression of the CNV size [149]. We reported no significant modification of B2R mRNA and protein expression in human neovascular AMD retinae [93].…”

“…An expression of TK, B1R, and B2R was also reported at multiple tissue sites in the anterior portion of the human eye [96]. Nevertheless, B2R but not B1R was expressed in the control human retinae [93]. BK produces B2R-mediated vasodilatation of retinal vessels in control rats [97].…”

“…Similarly to other organs, the KKS in the eye is a double-edged sword, as it contributes to many physiological processes including blood-flow regulation and vascular tone control, but also partakes in the complex processes of inflammation [4,57,89]. It was reported that the KKS underlies a number of ocular pathologies (DR, AMD, choroidal neovascularization, macular edema) associated with inflammation and pathological neovascularization, particularly in the human and rat retina [57][58][59][60]69,[90][91][92][93]. For instance, PK and HK, by binding to the vascular endothelium, release BK and subsequently activate B2R, which plays a key role in the control of vascular tone [4].…”

“…Importantly, these responses were reversed by eye-drop application of B1R antagonists (LF22-0542 and R-954) [58,60]. B1R was strongly expressed in vascular endothelial cells and in the retinal pigment epithelium of human and rats' retinae, suggesting its implication in altering the integrity of the internal and external blood-retinal barrier (BRB) in DR and AMD [58,59,69,92,93]. B1R might disrupt the BRB [59,60,69] either by the suppression of tight junction components (occludin, claudin, and zonula occludens-1), or by a rearrangement of the cytoskeleton filamentous actin [121].…”