Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats.

Evans, Terry; Deng, Diana Xi; Chen, Shali; Chakrabarti, Subrata

doi:10.2337/diabetes.49.4.662

Cited by 96 publications

(110 citation statements)

References 28 publications

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“…4,15,18 We have also shown that hyperhexosemia-induced increased FN mRNA expression can be prevented by bosentan treatment in retinas and kidneys of both diabetic and galactose-fed rats. 4,15 Bosentan treatment also prevented retinal capillary and glomerular basement membrane thickening in these animals. Furthermore, a similar normalization of FN expression by bosentan has been shown in heart tissues of diabetic animals.…”

Section: Discussionmentioning

confidence: 67%

“…[1][2][3][4][5]18 We have previously demonstrated an important role of hyperglycemia-induced ET-1 expression in increased ECM protein deposition. 4,15,18 We have also shown that hyperhexosemia-induced increased FN mRNA expression can be prevented by bosentan treatment in retinas and kidneys of both diabetic and galactose-fed rats. 4,15 Bosentan treatment also prevented retinal capillary and glomerular basement membrane thickening in these animals.…”

Section: Discussionmentioning

confidence: 99%

“…One predominant ECM protein that has been shown to be upregulated in diabetic angiopathy is fibronectin (FN). [3][4][5][6] FN is a glycoprotein of 250 kDa, which in addition to being one of the most abundant proteins in the ECM, is also one of the most specialized. 7 FN molecules interact with various matrix proteins and also modulate numerous cellular processes by interacting with cell surface receptors.…”

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confidence: 99%

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Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

Xin

Khan

Chen

et al. 2004

Laboratory Investigation

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Increased extracellular matrix protein deposition and basement membrane thickening are important features of diabetic angiopathy. One key matrix protein that has been shown to be instrumental in basement membrane thickening is fibronectin (FN). We have previously demonstrated that glucose-induced increased expression of endothelin-1 (ET-1), may in part, be responsible for increased FN expression via nuclear factor-jB (NF-jB) and activating protein (AP-1) activation. The present study was aimed at elucidating the mechanism of ET-1 with respect to mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation and glucose-induced FN upregulation. Human endothelial cells were exposed to either low (5 mM) or high (25 mM) glucose levels. Cells in low glucose were also treated with ET-1 peptide (5 nM). In addition, we treated cells exposed to high glucose levels with specific MAPK/ERK inhibitor PD098059 (50 lM), dual ETreceptor antagonist, bosentan (10 lM), and PKC blocker, chelerythrine (1 lM). Following incubation period, RNA and total proteins were extracted for RT-PCR for FN and immunoblot analysis of MAPK/ERK activation. Confocal microscopy was performed for analysis of FN protein and nuclear localization of activated Elk. Electrophoretic mobility shift assay was carried out to detect NF-jB and AP-1 activation. Our data demonstrates that high glucose-induced upregulation of FN messenger RNA and protein levels occur via activation of MAPK/ ERK pathway, which was prevented by treatment of cells with bosentan, PD098059 and PKC blocker chelerythrine. Confocal microscopy demonstrated nuclear localization of phospho-Elk protein. Glucoseinduced FN expression was also associated with protein kinase C, NF-jB, and AP-1 activation. These results suggested that glucose-induced, ET-and PKC-dependent, upregulation of FN is, in part, mediated via MAPK/ ERK activation.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

Xin

Khan

Chen

et al. 2004

Laboratory Investigation

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“…It is generally recognized that basement membrane thickening is a hallmark of diabetic microvasculopathy, and inappropriate upregulation of the component mRNAs and proteins is thought to be a major factor contributing to this lesion (43)(44)(45). AGEs accumulate on diabetic retinal capillary basement membranes (14) where they are thought to contribute to structural and functional abnormalities on this specialized ECM, including rendering it more resistant to protease modification (46 -48).…”

Section: Discussionmentioning

confidence: 99%

The AGE Inhibitor Pyridoxamine Inhibits Development of Retinopathy in Experimental Diabetes

et al. 2002

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We examined the ability of pyridoxamine (PM), an inhibitor of formation of advanced glycation end products (AGEs) and lipoxidation end products (ALEs), to protect against diabetes-induced retinal vascular lesions. The effects of PM were compared with the antioxidants vitamin E (VE) and R-␣-lipoic acid (LA) in streptozotocin-induced diabetic rats. Animals were given either PM (1 g/l drinking water), VE (2,000 IU/kg diet), or LA (0.05%/kg diet). After 29 weeks of diabetes, retinas were examined for pathogenic changes, alterations in extracellular matrix (ECM) gene expression, and accumulation of the immunoreactive AGE/ALE N -(carboxymethyl)lysine (CML). Acellular capillaries were increased more than threefold, accompanied by significant upregulation of laminin immunoreactivity in the retinal microvasculature. Diabetes also increased mRNA expression for fibronectin (2-fold), collagen IV (1.6-fold), and laminin ␤ chain (2.6-fold) in untreated diabetic rats compared with nondiabetic rats. PM treatment protected against capillary drop-out and limited laminin protein upregulation and ECM mRNA expression and the increase in CML in the retinal vasculature. VE and LA failed to protect against retinal capillary closure and had inconsistent effects on diabetes-related upregulation of ECM mRNAs. These results indicate that the AGE/ALE inhibitor PM protected against a range of pathological changes in the diabetic retina and may be useful for treating diabetic retinopathy.

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“…*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%

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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Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats.

Cited by 96 publications

References 28 publications

Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

The AGE Inhibitor Pyridoxamine Inhibits Development of Retinopathy in Experimental Diabetes

Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

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