Abstract
BackgroundInflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα).Methodology/Principal FindingsExpression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE−/−) and TNFα deficient (TNFα−/−, ApoE−/−/TNFα−/−) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE−/− than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE−/− mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides.Conclusions/SignificanceHyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE−/− mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes.
Highlights
The pathogenesis of diabetic retinopathy has lately been recognized to involve low-grade, chronic inflammation[1,2,3], proposed to be the result of persistent hyperglycemia as well as of dyslipidemia[1,4,5]
The present study investigated early retinal endothelial activation in diabetes and/or dyslipidemia by assessment of vascular cellular adhesion molecule-1 (VCAM-1) expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-a (TNFa)
Our major findings are as follows: (1) VCAM-1 protein levels were increased in retinal vessels of wt mice after 8 weeks of diabetes, at a time-point when the expression of the inflammatory cytokines TNFa, IL-6 and IL-1b was elevated in retina and levels of soluble VCAM-1 (sVCAM-1) in plasma were higher; (2) TNFa2/2 deficient mice exhibited higher basal levels of VCAM-1 protein in retinal vessels and sVCAM-1 in plasma than wt mice, but failed to up-regulate IL-6 and IL-1b mRNA and VCAM-1 protein in response to diabetes
Summary
The pathogenesis of diabetic retinopathy has lately been recognized to involve low-grade, chronic inflammation[1,2,3], proposed to be the result of persistent hyperglycemia as well as of dyslipidemia[1,4,5]. Up-regulation of inflammatory mediators and adhesion molecules are early features of diabetic retinopathy[6], leading to accumulation of leukocytes, altered vessel reactivity and subsequent activation of receptors and transcription factors, resulting in apoptosis or proliferation of various cell types in the retina[5,7], e.g., loss of pericytes and proliferation of endothelial cells. In type 2 diabetic subjects (T2D), serum levels of sVCAM-1 and sE-selectin are increased both in patients with micro- and macrovascular complications, whereas sICAM-1 levels are higher only in the microvascular group[19] This suggests potential differential regulation of adhesion molecules and maybe differential functions. We investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-a (TNFa)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
