A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood‐retinal barrier in diabetes

Navaratna, Deepti; Menicucci, G.; Maestas, Joann; Srinivasan, Ramprasad; McGuire, Paul; Das, Arup

doi:10.1096/fj.08-110155

Cited by 37 publications

(39 citation statements)

References 34 publications

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“…Diabetes/high glucose-induced increases in MMP9 activity in retinal tissues in vivo and retinal endothelial cells in vitro and alterations in composition of the perivascular extracellular matrix have been linked to retinal vascular injury and compromised barrier function [35–38]. Previous studies have also implicated increases in uPA and MMP expression and activities in breakdown of the blood retinal barrier [15,20,30,39,40]. Investigations using cultured retinal endothelial cells have shown that treatment with exogenous MMP9 and uPA causes an increase in paracellular permeability by a mechanism involving decreases in the tight junction protein occludin [14,26].…”

Section: Discussionmentioning

confidence: 99%

“…This leads to degradation of the extracellular matrix and disruption of cell-cell and cell-matrix attachments. The role of this proteolytic cascade in diabetes-induced breakdown of the blood-retinal barrier has been supported by studies showing that treatment with inhibitors of MMP or uPA blocks diabetes-induced breakdown of the BRB [15,20], but the upstream mediators of this process are as yet unknown.…”

Section: Introductionmentioning

confidence: 99%

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Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway

et al. 2013

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Diabetes-induced breakdown of the blood-retinal barrier (BRB) has been linked to hyperglycemia-induced expression of vascular endothelial growth factor (VEGF) and is likely mediated by an increase in oxidative stress. We have shown that VEGF increases permeability of retinal endothelial cells (REC) by inducing expression of urokinase plasminogen activator receptor (uPAR). The purpose of this study was to define the role of superoxide anion in VEGF/uPAR expression and BRB breakdown in diabetes. Studies were performed in streptozotocin diabetic rats and mice and high glucose (HG) treated REC. The superoxide dismutase (SOD) mimetic tempol blocked diabetes-induced permeability and uPAR expression in rats and the cell permeable SOD inhibited HG-induced expression of uPAR and VEGF in REC. Inhibiting VEGFR blocked HG-induced expression of VEGF and uPAR and GSK-3β phosphorylation in REC. HG caused β-catenin translocation from the plasma membrane into the cytosol and nucleus. Treatment with HG-conditioned media increased REC paracellular permeability that was blocked by anti-uPA or anti-uPAR antibodies. Moreover, deletion of uPAR blocked diabetes-induced BRB breakdown and activation of MMP-9 in mice. Together, these data indicate that diabetes-induced oxidative stress triggers BRB breakdown by a mechanism involving uPAR expression through VEGF-induced activation of the GSK3β/β-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway

et al. 2013

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“…Increased BRB permeability results in the excess accumulation extracellular fluid and hard exudates in the macula leading to the development of diabetic macular edema and loss of central vision. 5,6 …”

Section: Introductionmentioning

confidence: 99%

LRP-1 Pathway Targeted Inhibition of Vascular Abnormalities in the Retina of Diabetic Mice

Hossain

Tauhid

Davenport

et al. 2016

Current Eye Research

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Purpose The cell surface LDL (low-density lipoprotein) receptor-related protein-1 (LRP-1) is important for lipid transport and several cell signaling processes. Human apolipoprotein E (apoE) is a ligand of LRP-1. We previously reported that a short peptide (apoEdp) mimicking the LRP-1 binding region of apoE prevents hyperglycemia-induced retinal endothelial cell dysfunction in vitro. The in-vivo outcome of apoE-based peptidomimetic inhibition of LRP-1 in the treatment of diabetic retinopathy is unknown. Methods Six months after streptozotocin induction of diabetes, male C57Bl/6 mice were intravitreally inoculated with apoEdp in a controlled release formulation. On the 15th day post-apoEdp treatment, mouse retinas were harvested to examine (1) blood–retinal–barrier (BRB) permeability by Evans blue dye, inflammatory leukostasis by concanavalin staining of leukocytes and LRP-1 pathway-related protein expression by Western blot analysis and gelatin zymography. Results Intravitreal apoEdp treatment of diabetic mice significantly reduced Evans blue extravasation and the number of adherent leukocytes in the diabetic mouse retinas. ApoEdp treatment inhibited the expression of extracellular matrix (ECM) degrading proteases heparanase and MMP-2, and restores the BRB tight junction proteins occludin and ZO-1. ApoEdp treatment also inhibited Wnt/β-catenin-related expression of pro-inflammatory molecules ICAM-1, HIF-1α, and VEGF through negative regulation by LRP-1. Conclusion Intravitreal apoEdp treatment of diabetic mice resulted a significant decrease in retinal vascular abnormalities through downregulation of LRP-1-related ECM protein degradation and Wnt/β-catenin-related pro-angiogenic molecules.

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“…In addition, Å6 demonstrated promising therapeutic effects in other pathological experimental models. For instance, Å6 inhibited the degradation of vascular endothelial cadherin and elevated the alteration of the blood retinal barrier in diabetic rats 98 . In a laser-induced choroidal neovascularization mouse model, Å6 suppressed 95% of vascular formation 99 .…”

Section: Upar Antagonists As Anticancer or Anti-inflammatory Agentsmentioning

confidence: 94%

Therapeutics targeting the fibrinolytic system

Lin

Lu-ning

et al. 2020

Exp Mol Med

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The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed.

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A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood‐retinal barrier in diabetes

Cited by 37 publications

References 34 publications

Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway

Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway

LRP-1 Pathway Targeted Inhibition of Vascular Abnormalities in the Retina of Diabetic Mice

Therapeutics targeting the fibrinolytic system

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