Journal Article

Effects of Nox4 upregulation on PECAM-1 expression in a mouse model of diabetic retinopathy

Wang, Jinli, Wang, Joshua J., Zhang, Sarah X., Lai, Daniel A.

2024

Overview

Diabetic Retinopathy (DR) is the leading cause of vision loss in working-age adults. The hallmark features of DR include vascular leakage, capillary loss, retinal ischemia, and aberrant neovascularization. Although the pathophysiology is not fully understood, accumulating evidence supports elevated reactive oxygen species associated with increased activity of NADPH oxidase 4 (Nox4) as major drivers of disease progression. Previously, we have shown that Nox4 upregulation in retinal endothelial cells by diabetes leads to increased vascular leakage by an unknown mechanism. Platelet endothelial cell adhesion molecule 1 (PECAM-1) is a cell surface molecule that is highly expressed in endothelial cells and regulates endothelial barrier function. In the present study, using endothelial cell-specific human Nox4 transgenic (TG) mice and endothelial cell-specific Nox4 conditional knockout (cKO) mice, we investigated the impact of Nox4 upregulation on PECAM-1 expression in mouse retinas and brain microvascular endothelial cells (BMECs). Additionally, cultured human retinal endothelial cells (HRECs) transduced with adenovirus overexpressing human Nox4 were used in the study. We found that overexpression of Nox4 increases PECAM-1 mRNA but has no effect on its protein expression in the mouse retina, BMECs, or HRECs. Furthermore, PECAM-1 mRNA and protein expression was unchanged in BMECs isolated from cKO mice compared to wild type (WT) mice with or without 2 months of diabetes. Together, these findings do not support a significant role of Nox4 in the regulation of PECAM-1 expression in the diabetic retina and endothelial cells. Further studies are warranted to elucidate the mechanism of Nox4-induced vascular leakage by investigating other intercellular junctional proteins in endothelial cells and their implications in the pathophysiology of diabetic retinopathy.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenoviruses / Animals / Antibodies / Biology and Life Sciences / Blood vessels / Brain research / CD31 antigen / Cell adhesion / Cell adhesion molecules / Cell death / Cell surface / Computer and Information Sciences / Development and progression / Diabetes / Diabetes mellitus / Diabetic retinopathy / Diabetic Retinopathy - genetics / Diabetic Retinopathy - metabolism / Diabetic Retinopathy - pathology / Disease Models, Animal / Edema / Endothelial cells / Endothelial Cells - metabolism / Endothelium / Engineering and Technology / Gene expression / Genetic engineering / Health aspects / Humans / Inflammation / Ischemia / Leakage / Medicine and Health Sciences / Mice / Mice, Knockout / Mice, Transgenic / Microvasculature / mRNA / NAD(P)H oxidase / NADH dehydrogenase / NADPH Oxidase 4 - genetics / NADPH Oxidase 4 - metabolism / NADPH Oxidases - genetics / NADPH Oxidases - metabolism / NOX4 protein / Oxidases / Oxidative stress / Pathogenesis / Pathophysiology / Permeability / Physiological aspects / Platelet Endothelial Cell Adhesion Molecule-1 - genetics / Platelet Endothelial Cell Adhesion Molecule-1 - metabolism / Proteins / R&D / Reactive oxygen species / Research & development / Research and Analysis Methods / Retina / Retina - metabolism / Retina - pathology / Retinopathy / RNA / Signal transduction / Transgenic mice / Up-Regulation / Vascularization