Roles of endothelin-1 and selected proinflammatory cytokines in the pathogenesis of proliferative diabetic retinopathy: Analysis of vitreous samples
Introduction
Various mechanism have been proposed to explain how hyperglycaemia and components of metabolic syndrome can affect endothelial function in diabetes [1], [2], [3], [4]. An increase in intracellular glucose will lead to an increase in the flux of glucose to sorbitol via the polyol pathway, an increase in glucosamine-6-phosphativie through the hexosamine pathway, and the activation of PKC (protein kinase C) via de novo synthesis of DAG (diacyloglicerol). In addition, glucose and glucose-derived dicarbonyl compounds react non-enzymatically with the basic amino acids lysine and arginine in proteins to form AGEs. These different pathways are interrelated and potentiate each other [5], [6]. These disturbances are undoubtedly involved in the pathogenesis of diabetic retinopathy. The DAG/PKC pathway determines blood flow dysregulation by decreasing endothelial NOS activity and/or increasing the synthesis of ET-1, one of the strongest vasoconstrictive factors [7]. In diabetic animals, an oral PKC-β inhibitor prevented diabetes-induced abnormalities in the mRNA expressions of TGF-β1, type IV collagen, and fibronectin [8].
It is necessary to emphasize the fact that ET-1 acts on different vascular areas with different strength [9]. Therefore, various vessels’ response to the activity of this factor may result from different concentrations of receptors on the vessel wall [10]. Observations indicate that the participation of endothelin in coagulation disorders is also essential for the development of PDR (proliferative diabetic retinopathy). Authors [11] point out the fact that thrombosis in the rat microcirculation and a DIC-like process in the rabbit circulation develop under the influence of ET-1. An important element in the development of this disturbance is the documented MAPK (mitogen-activated protein kinase)-dependent ET-1 production [12].
Non-enzymatic glycation of proteins can interfere with endothelial functions in several ways [13], [14]. It is a prominent activation pathway of proinflammatory cytokine synthesis and of growth factors such as IL-1, IL-6, TNF-α, VEGF, and TGF-β [15], [16], [17]. Inflammatory cytokines increase vascular permeability, alter vasoregulatory responses, increase leukocyte adhesion to endothelium, and facilitate thrombus formation by inducing pro-coagulant activity and inhibiting anti-coagulant pathways [18]. Transcription factor NF-kB, the main pathway for the cytokine regulation of gene expression in endothelial cells, is activated not only by TNF-α, IL-1, and IL-6, but also by hyperglycaemia, AGEs, oxidized lipids, and insulin [5].
The aim of this analysis of patients with clinical proven PDR was to establish the role of the inflammatory-proliferative process of the endothelium in the pathogenesis of this diabetic complication on the basis of ET-1, TNF-α, and IL-6 concentration measurement in the vitreous body obtained intraoperatively. The obtained data were analysed in the context of endothelium damage (vWF, sE-selectin) and the clinical course of type 2 diabetes.
Section snippets
Research design and methods
Nineteen patients with PDR during the course of type 2 diabetes (12 women and 7 men) at ages between 49 and 79 (average: 64.63 ± 8.38 years) (Table 1) were included in this study. Average disease duration was 2.47 ± 6.75 years. All patients who were qualified for the study were receiving human insulin in a program of intensive insulin therapy, oral antidiabetic drugs, statins, and inhibitors of angiotensin-converting enzyme (iACEs). The extent of metabolic disturbances in diabetes exceeded the target
Results
Table 1 presents the clinical characteristics of the patients participating in the study.
Discussion
In this study, the mean vitreous ET-1 level in the PDR patients was significantly higher than in the control group, by a factor or two, and the blood concentration by a factor of seven. This seems to exclude the possibility of a passive influx of this factor from the systemic circulation to the retina through disruption of the blood-retinal barrier. This suggestion is strongly confirmed by the comparable values of the vitreous/plasma ET-1 concentration ratios of 7.18 ± 194 and 7.00 ± 0.89 fmol/ml in
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