Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion.

Morigi, Marina; Angioletti, Stefania; Imberti, Barbara; Donadelli, Roberta; Micheletti, Gianluca; Figliuzzi, Marina; Remuzzi, Andrea; Zoja, Carla; Remuzzi, Giuseppe

doi:10.1172/jci656

Cited by 409 publications

(295 citation statements)

References 49 publications

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“…[28][29][30] FN gene has both NF-kB and AP-1 binding site on its promoter and may be positively regulated by both transcription factors. [31][32][33][34][35] Data from our present study would suggest that MAPK pathway may upregulate FN via NF-kB and AP-1. However, it is possible that glucose-induced PKC and ET-1 activation may also lead to FN upregulation independent of MAPK activation.…”

Section: Discussionmentioning

confidence: 52%

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: 52%

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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“…This radical-scavenging activity could be one of the mechanism of the inhibition of leukostasis observed in this study, because leukocytes in diabetic animals have been reported to be more activated [1,4] and produce more oxygen-derived free radicals [5,6], which induce vascular endothelial dysfunction [7,8,9]. Recent studies demonstrated the increased expression of adhesion molecules under diabetic conditions [2,7,10,26,35]. The interference by gliclazide with the increase in adhesion molecule expression could be another possibility, although it has not been examined in this study.…”

Section: Discussionmentioning

confidence: 76%

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Kinoshita¹,

Kakehashi²,

Inoda

et al. 2002

Diabetologia

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Aims/hypothesis. Early stage leukocyte entrapment in the retinal microcirculation (retinal leukostasis) is considered to be one of the important pathogenetic events in diabetic retinopathy. Gliclazide, a sulphonylurea, was reported to reduce leukocyte adhesion to endothelial cells in hyperglycaemia in vitro, thus suggesting possible selective efficacy of this sulphonylurea in preventing leukostasis in diabetic patients. This study evaluated the effectiveness and selectivity of gliclazide treatment on retinal leukostasis of diabetic rats in vivo. Methods. Streptozotocin (STZ) (65 mg/kg)-induced diabetic rats were divided into three groups (n = 8 each): an untreated diabetic group, a gliclazide-treated diabetic group, and a glibenclamide-treated diabetic group. Gliclazide or glibenclamide was administered orally during a 3-week period. Non-diabetic rats were used as a control (n = 8). Retinal leukostasis was quantitatively evaluated in vivo by acridine orange leukocyte fluorography using a scanning laser ophthalmoscope.Results. The number of leukocytes trapped in the area around the optic disc in the untreated diabetic group (36.9 ± 5.1 cells) increased significantly compared with the non-diabetic control group (21.9 ± 2.9 cells; p = 0.0007). The number of leukocytes trapped in the gliclazide-treated diabetic group (23.5 ± 4.0 cells) decreased significantly compared with untreated diabetic group (p = 0.0008). In contrast, no reduction of retinal leukostasis was found in the glibenclamide-treated diabetic group (37.8 ± 5.8 cells; p = 0.7923). Conclusion/interpretation. This suggests that gliclazide could directly improve abnormalities in the retinal microcirculation independent of blood glucose control and possibly have selective therapeutic benefits in preventing early, critical events in diabetic retinopathy compared with other sulphonylurea drugs. [Diabetologia (2002) 45:735-739] Keywords Gliclazide, sulphonylurea, diabetic retinopathy, retinal leukostasis, acridine orange leukocyte fluorography, scanning laser ophthalmoscope. Diabetic retinopathy is a leading cause of adult vision loss and blindness and early-stage, preventive strategies are important research areas. Leukocyte adhesion to the diabetic retinal vasculature is presumed to be the critical early event in the pathogenesis of diabetic retinopathy [1,2,3], resulting in a breakdown in the blood-retinal barrier and in capillary nonperfusion [1,4,5,6,7,8,9,10,11,12]. In a rat model of diabetic retinopathy, investigators demonstrated retinal capillary occlusion by neutrophils and monocytes in histologic sections and found that areas of endothelial cell damage, capillary loss, and leukocyte extravasation existed adjacent to the static leukocytes [1]. In another post mortem study of human subjects, increased numbers of neutrophils were observed in the choroid and retina of patients with diabetes [2].

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“…This effect was independent of increases in serum insulin levels. Several studies have assessed the relation between hyperglycaemia and leucocyte binding to endothelial cells [14][15][16][17]. Although these studies used various experimental conditions and have their own meanings depending on the experimental conditions, most in vivo and in vitro studies have shown that hyperglycaemia induces leucocyte adhesion to endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta

et al. 2005

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Aims/hypothesis: Several epidemiological data suggest that patients with postprandial hyperglycaemia are at high risk of cardiovascular disease. The aim of this study was to elucidate the effect of a glucose 'spike' on monocyte adhesion to rat aortic endothelial cells. Materials and methods: Monocyte adhesion to endothelial cells in vivo was quantitated using an en face method for observation of endothelial surface after immunohistochemical staining for CD68 in the thoracic aortas of Sprague-Dawley rats after several kinds of blood glucose rises. Results: The number of monocytes adhering to endothelial cells increased at 30 min after injection of glucose in 8-week-old Sprague-Dawley rats. The increased adhesion returned to the basal level at 120 min after glucose injection, concomitantly with the return of blood glucose levels to normal. The infusion of octreotide to inhibit endogenous insulin secretion did not prevent the glucose-induced increase in monocyte adhesion to endothelial cells. On the other hand, the number of monocytes adhering to endothelial cells did not increase in rats with streptozotocin-induced diabetes and sustained hyperglycaemia. Conclusions/interpretation: Our data demonstrate that a temporary rise in blood glucose levels can in itself promote a reversible increase in monocyte adhesion to arterial endothelial cells.

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Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion.

Cited by 409 publications

References 49 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

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta

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