Concentrations of Selected Cytokines and Vascular Endothelial Growth Factor in Aqueous Humor and Serum of Diabetic Patients

Cvitkovic, Katarina; Sesar, Antonio; Sesar, Irena; Pusic-Sesar, Anita; Pejic, Renato; Kelava, Tomislav; Šućur, Alan; Ćavar, Ivan

doi:10.1080/08820538.2020.1755320

Cited by 13 publications

(24 citation statements)

References 30 publications

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“…VEGF is secreted ubiquitously inside the retina and its expression is also modulated by high glucose [28]. It induces both increased iBRB permeability and angiogenesis, two major events of DR, and its expression is augmented in the vitreous and aqueous humor of DR patients [30]. Consistently with previous findings, our results show a major increase of HIF-1 in ECs cultivated in hyperglycemic and hypoxic conditions, with a consequent rise of VEGF.…”

Section: Discussionsupporting

confidence: 92%

“…MCP-1 acts as a potent inflammatory factor inside the retina, released mostly by Müller cells, its levels correlating with VEGF production, changes in BRB permeability, leukocyte recruitment, and induction of superoxide from monocytes/macrophages [25]. Its expression is increased in patients with ocular diseases, such as DR [30]. Consistently, we found a decrease in PDGF-B in ECs cultured in fluctuating glucose concentrations, corrected by thiamine supplementation, and increased MCP-1 release by pericytes and Müller cells, normalized by FA addition.…”

Section: Discussionmentioning

confidence: 99%

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Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier

et al. 2020

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Aims: Although diabetic retinopathy has long been considered a microvascular complication, retinal neurodegeneration and inflammation may precede its clinical manifestations. Despite all research efforts, the primary treatment options remain laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections, both aggressive and targeting the late stages of the disease. Medical treatments addressing the early phases of diabetic retinopathy are therefore needed. We aimed at verifying if thiamine and fenofibrate protect the cells of the inner blood-retinal barrier from the metabolic stress induced by diabetic-like conditions. Methods: Human microvascular endothelial cells (HMECs), retinal pericytes (HRPs) and Müller cells (MIO-M1) were cultured in intermittent high glucose (intHG) and/or hypoxia, with addition of fenofibrate or thiamine. Modulation of adhesion molecules and angiogenic factors was addressed. Results: Integrins β1/αVβ3 and ICAM1 were upregulated in HMECs/HRPs cultured in diabetic-like conditions, as well as metalloproteases MMP2/9 in HRP, with a reduction of their inhibitor TIMP1; MMP2 increased also in HMEC, and TIMP1 decreased in MIO-M1. VEGF and HIF-1α were strongly increased in HMEC in intHG+hypoxia, and VEGF also in HRP. Ang-1/2 augmented in HMEC/MIO-M1, and MCP-1 in HRP/MIO-M1 in intHG+hypoxia. Thiamine was able to normalize all such abnormal modulations, while fenofibrate had effects in few cases only. Conclusions: We suggest that endothelial cells and pericytes are more affected than Müller cells by diabetic-like conditions. Fenofibrate shows a controversial behavior, potentially positive on Müller cells and pericytes, but possibly detrimental to endothelium, while thiamine confirms once more to be an effective agent in reducing diabetes-induced retinal damage.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier

et al. 2020

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“…Higher serum levels of IL-6 were also shown in patients with T2DM and proliferative diabetic retinopathy rather than in the group of patients with T2DM without complications [32,33]. The presence of chronic inflammatory environment in the course of diabetes increases the expression of inflammatory factors, also in the aqueous humour of the eye [22,34]. The eight following factors have been recently found in the aqueous humour of DR patients: interleukin IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) [13].…”

Section: The Retina-hyperglycaemia and Inflammation In The Course Of mentioning

confidence: 99%

Retinal Vascular Endothelial Cell Dysfunction and Neuroretinal Degeneration in Diabetic Patients

Mrugacz

Bryl

Zorena

2021

JCM

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Diabetes mellitus (DM) has become a vital societal problem as epidemiological studies demonstrate the increasing incidence of type 1 and type 2 diabetes. Lesions observed in the retina in the course of diabetes, referred to as diabetic retinopathy (DR), are caused by vascular abnormalities and are ischemic in nature. Vascular lesions in diabetes pertain to small vessels (microangiopathy) and involve precapillary arterioles, capillaries and small veins. Pericyte loss, thickening of the basement membrane, and damage and proliferation of endothelial cells are observed. Endothelial cells (monolayer squamous epithelium) form the smooth internal vascular lining indispensable for normal blood flow. Breaking its continuity initiates blood coagulation at that site. The endothelium controls the process of exchange of chemical substances (nutritional, regulatory, waste products) between blood and the retina, and blood cell passing through the vascular wall. Endothelial cells produce biologically active substances involved in blood coagulation, regulating vascular wall tension and stimulating neoangiogenesis. On the other hand, recent studies have demonstrated that diabetic retinopathy may be not only a microvascular disease, but is a result of neuroretinal degeneration. Neuroretinal degeneration appears structurally, as neural apoptosis of amacrine and Muller cells, reactive gliosis, ganglion cell layer/inner plexiform (GCL) thickness, retinal thickness, and retinal nerve fiber layer thickness, and a reduction of the neuroretinal rim in minimum rim width (MRW) and functionally as an abnormal electroretinogram (ERG), dark adaptation, contrast sensitivity, color vision, and microperimetric test. The findings in early stages of diabetic retinopathy may precede microvascular changes of this disease. Furthermore, the article’s objective is to characterize the factors and mechanisms conducive to microvascular changes and neuroretinal apoptosis in diabetic retinopathy. Only when all the measures preventing vascular dysfunction are determined will the risk of complications in the course of diabetes be minimized.

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“…Whereas several studies compared AH and serum concentrations of different cytokines in DR and control groups [ 54 , 55 ], only a few studies have attempted to correlate specific biomarkers to the severity of DR [ 56 , 57 ]. Although currently there exists no clear concept as to the regulation of the retinal environment and the source of the local cytokinome, available evidence seems in favor of local rather than systemic factors driving the pathogenesis and progression of both DR and DME [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Ocular TGF-β, Matrix Metalloproteinases, and TIMP-1 Increase with the Development and Progression of Diabetic Retinopathy in Type 2 Diabetes Mellitus

Saucedo

Pfister

Zandi

et al. 2021

Mediators of Inflammation

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Diabetic retinopathy (DR) is a sight-threatening late complication of diabetes mellitus (DM). Even though its pathophysiology has not been fully elucidated, several studies suggested a role for transforming growth factor- (TGF-) β, matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinase (TIMP) in the onset and progression of the disease. Consequently, the aim of this study was to analyze the concentrations of TGF-β1, TGF-β2, TGF-β3, MMP-3, MMP-9, and TIMP-1 in patients with different stages of DR in order to identify stage-specific changes in their concentrations during the progression of the disease. Serum and aqueous humor (AH) samples were collected during intraocular surgery, and eyes were classified into the following groups: healthy controls ( n = 17 ), diabetic patients with non-apparent DR ( n = 23 ), mild/moderate nonproliferative DR (NPDR) ( n = 13 ), and advanced NPDR/proliferative DR (PDR) without vitreal hemorrhage ( n = 14 ). None of the patients had been under anti-VEGF or laser treatment within six months prior to surgery. In the AH, TGF-β1 levels increased in advanced NPDR/PDR by a factor of 5.5 compared to the control group. Similarly, an increase in MMP-3 and TIMP-1 levels in the AH was evident in the later stages of DR, corresponding to a 7.7- and 2.4-fold increase compared to the control group, respectively, whereas serum levels of the studied proteins remained similar. In conclusion, increased concentrations of TGF-β1, MMP-3, and TIMP-1 in the AH, but not in the serum, in advanced NPDR/PDR indicate that the intraocular regulation for these cytokines is independent of the systemic one and suggest their involvement in the progression of DR.

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Concentrations of Selected Cytokines and Vascular Endothelial Growth Factor in Aqueous Humor and Serum of Diabetic Patients

Cited by 13 publications

References 30 publications

Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier

Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier

Retinal Vascular Endothelial Cell Dysfunction and Neuroretinal Degeneration in Diabetic Patients

Ocular TGF-β, Matrix Metalloproteinases, and TIMP-1 Increase with the Development and Progression of Diabetic Retinopathy in Type 2 Diabetes Mellitus

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