Histamine H₄ receptor as a therapeutic target for inner/outer BRB disruption in STZ-induced diabetic mice

Abstract

Purpose : Histamine is implicated in the pathogenesis of diabetes and is suggested to be involved in the progression of diabetic microvascular complications, such as diabetic retinopathy (DR). Previous reports suggest that the histamine/histamine receptor H4 axis (HRH4) is activated in the eyes with diabetic retinopathy patients. However, the efficacy of blocking the histamine/histamine receptor H4 axis in the development of diabetic retinopathy remains unclear. The aim of this study was to investigate therapeutic efficacy of histamine receptor H4 antagonist in streptozotocin (STZ)-induced diabetic retinopathy mouse model.

Methods : Immunofluorescence staining, and a fluorescence-labeled dextran vascular leakage test were conducted to evaluate whether blocking the histamine/HRH4 axis via daily oral treatment of HRH4 antagonist suppresses inner and outer blood-retinal barrier (BRB) disruption and vascular leakage in early (4 weeks) and late-stage (16 weeks) of STZ-induced diabetic retinopathy mouse model.

Results : HRH4 was overexpressed in retina and RPE tissues in STZ-induced diabetic mice at 4 weeks and 16 weeks post-diabetes than control mice. Vascular leakage of inner and outer retina, astrocyte loss, pericyte loss, and tight junction disruption of retinal pigment epithelium (RPE) reflecting inner and outer BRB disruption were observed at 4 weeks and 16 weeks post-diabetes. We found that daily HRH4 antagonist oral treatment effectively suppressed vascular leakage of inner and outer retina, loss of astrocyte and pericyte, and tight junction disruption of RPE at 4 weeks and 16 weeks post-diabetes in STZ-induced diabetic mice.

Conclusions : Our results suggest that histamine/HRH4 axis is activated in the eyes with diabetic retinopathy and regulation of histamine/HRH4 axis could be a potential therapeutic target in diabetic retinopathy.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.