Diabetic retinopathy is a leading cause of visual impairment among working-age adults. Given the multiple pathophysiologic functions of bradykinin and its links to vascular endothelial growth factor (VEGF) and atrial natriuretic peptide (ANP) signaling, we hypothesized their interconnected involvement in the development of retinal vascular permeability in early-stage diabetic retinopathy. Diabetic mice, bradykinin type 2 receptor (B2R) knock-out diabetic mice, and their non-diabetic controls underwent magnetic resonance imaging, fluorescein angiography, vascular permeability measurements, retinal ELISA, Western blot, qPCR, and immunohistochemistry, glycemic assessments, and evaluation of intraocular and blood pressure. Diabetes upregulated B2R expression without altering retinal bradykinin levels. B2R deficiency in diabetic mice unexpectedly exacerbated vascular permeability but ameliorated retinal thinning and ganglion cell loss. B2R-deficient animals had decreased VEGF and VEGF receptor-2 levels, despite increased gene expression, indicating a regulatory effect on protein synthesis. Both diabetes and B2R deficiency, especially the latter, increased ANP and guanylyl cyclase/natriuretic peptide receptor-A levels and their gene expression. This study provides new insights into the interplay between bradykinin, VEGF, and ANP in diabetic retinopathy. It highlights a regulatory role of B2R in VEGF and ANP signaling, suggesting targets for future research on vascular permeability and neuroprotection in early-stage diabetic retinopathy.
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