Oncofetal Fibronectin in Diabetic Retinopathy

Khan, Zia A.; Cukiernik, Mark; Gonder, John R.; Chakrabarti, Subrata

doi:10.1167/iovs.03-0540

Cited by 70 publications

(97 citation statements)

References 44 publications

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“…We and others have previously demonstrated the upregulation of fibronectin mRNA in vascular endothelial cells exposed to high levels of glucose and in the target organs of diabetic complications, i.e. retina, kidney and heart [3,4]. We have further demonstrated that these alterations may, in part, be dependent on the hyperglycaemia-induced increase in the production of vasoactive factors such as endothelins (ETs) and subsequent activation of nuclear factor-κB (NF-κB) and activating protein-1 (AP-1) [8,9].…”

Section: Introductionmentioning

confidence: 83%

“…*p<0.05 vs control and respective LG; n=4 per treatment [28]. Increased production of ECM proteins, such as fibronectin, may be an important factor leading to the development of long-term changes such as angiogenesis in diabetic retinopathy [3,29]. Several biochemical anomalies induced by high glucose may activate Akt.…”

Section: Discussionmentioning

confidence: 99%

“…This imbalance is instrumental in producing the structural hallmark of diabetic complications, basement membrane thickening. One predominant ECM protein that is upregulated in diabetic angiopathy is fibronectin [3,4]. Fibronectin is a highly specialised glycoprotein of 250 kDa.…”

Section: Introductionmentioning

confidence: 99%

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Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

et al. 2005

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Aims/hypothesis: Increased expression and decreased degradation of extracellular matrix (ECM) proteins are key features of chronic diabetic complications. Fibronectin, a predominant ECM protein, has been shown to be overexpressed in all target organs of diabetic complications and in endothelial cells cultured in high levels of glucose. The present study was designed to elucidate the role of protein kinase B (Akt/PKB) in glucose-induced fibronectin mRNA expression and protein production in vascular endothelial cells. Methods: Human umbilical vein endothelial cells were cultured in the presence of high glucose to study Akt/PKB activation. The upstream and downstream mediators in the Akt/PKB pathway were also investigated using dominant negative transfections and specific inhibitors of signalling pathways. Cells were subjected to real time RT-PCR, western blotting, and confocal microscopy to assess Akt1/PKBα activation and fibronectin mRNA expression and protein production. To detect transcription factor activation, electrophoretic mobility shift assay was carried out. Results: Our data demonstrate that fibronectin mRNA expression and protein production that are induced by high glucose are mediated via activation of Akt/PKB, which is modulated by mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase C. Glucose-induced fibronectin mRNA expression and protein production are also mediated by Akt1/PKBα-dependent activation of the transcription factors nuclear factor-κB and activating protein-1. Conclusions/interpretation: Our study provides insight into the mechanical basis of glucoseinduced increases in fibronectin mRNA expression and protein production. High levels of glucose may increase fibronectin mRNA expression and protein production by activating Akt/PKB.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

et al. 2005

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“…In vitro studies Human MVECs (Clonetics, Walkersville, MD, USA) were cultured with endothelial growth medium (Clonetics) as previously described [24]. To determine the optimal high glucose (HG) concentration, sub-confluent cells were incubated with 10, 15, 25 or 35 mmol/l D-glucose.…”

Section: Methodsmentioning

confidence: 99%

“…injection of streptozotocin (STZ; 65 mg/kg; Sigma-Aldrich) [24]. Ageand sex-matched controls were given an equal volume of citrate buffer.…”

Section: Methodsmentioning

confidence: 99%

Glucose-induced up-regulation of CD36 mediates oxidative stress and microvascular endothelial cell dysfunction

et al. 2005

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Aims/hypothesis: Hyperglycaemia-induced oxidative stress is implicated in the pathogenesis of chronic diabetic complications. Glucose-mediated oxidation of LDL may result in increased oxidative stress and vascular endothelial cell dysfunction via interaction with a cell surface scavenger receptor, CD36. In this study, we investigated the role of CD36 in cultured microvascular endothelial cells (MVECs) and in the heart by using an animal model of chronic diabetes. Methods: Cultured MVECs were subjected to varying glucose concentrations and assayed for alteration in CD36 gene expression and protein levels. To assess for oxidised LDL (ox-LDL) uptake, MVECs exposed to low and high glucose were treated with ox-LDL (80 μg/ml), a ligand for CD36. Haem oxygenase-1 (HO-1) and endothelin-1 (ET-1) induction, as well as oxidative stress were determined. The role of glucose-induced CD36 alteration in ox-LDL uptake was also assayed following post-transcriptional CD36 gene silencing. For in vivo studies, CD36 mRNA and oxidative DNA and protein damage were measured in heart tissues of 1-month-old diabetic Sprague-Dawley rats. Results: We found that glucose increased CD36 mRNA and protein levels in MVECs. High levels of glucose also augmented ox-LDL uptake, in association with increasing HO-1 and ET-1 mRNA levels. CD36 gene silencing prevented glucose-induced CD36 alteration, reduced ox-LDL uptake, and prevented HO-1 and ET-1 up-regulation. Similar to in vitro studies, diabetic heart tissues exhibited increased CD36 mRNA levels and increased oxidative DNA and protein damage. Conclusions/interpretation: Our results provide evidence that up-regulation of CD36 may have a role in increasing oxidative stress in MVECs and the heart in chronic diabetes.

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Ligand‐Based Vascular Targeting of Disease

et al. 2006

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This review illustrates the basic principles of ligand-based vascular targeting and presents some of the most advanced results obtained in this field, not only in terms of biopharmaceuticals, which are currently being investigated in clinical and preclinical studies, but also in terms of enabling technologies that facilitate target and ligand discovery. Whereas most of the vascular targeting research activities have so far concentrated on tumoral angiogenesis, the development of non-oncological applications has recently gained momentum and is likely to become an important area of modern pharmaceutical research.

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Oncofetal Fibronectin in Diabetic Retinopathy

Cited by 70 publications

References 44 publications

Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

Glucose-induced up-regulation of CD36 mediates oxidative stress and microvascular endothelial cell dysfunction

Ligand‐Based Vascular Targeting of Disease

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