Human Immunology

2006

DOI: 10.1016/j.humimm.2006.05.006

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NFκB and Its Inhibitor IκB in Relation to Type 2 Diabetes and Its Microvascular and Atherosclerotic Complications

Marianna Romzova

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Daniela Hohenadel

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Katarína Kološtová

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et al.

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Effects Of Fg On Nitrite Production and Inos Expression1

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Cited by 38 publications

(34 citation statements)

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“…Dysregulated NF-κB activation contributes to many immune-inflammatory diseases, including diabetes [6][7][8][9]. NF-κB gene polymorphisms influence the susceptibility to type 1 and 2 diabetes and affect microvascular and atherosclerotic complications in patients [13,28,29]. Hyperglycaemia, dyslipidaemia, oxidative stress and inflammation can also lead to the occurrence of diabetes complications by activating canonical NF-κB-driven genes [15].…”

Section: Resultsmentioning

confidence: 99%

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

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et al. 2015

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Aims/hypothesis The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis.Methods Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.

“…Dysregulated NF-κB activation contributes to many immune-inflammatory diseases, including diabetes [6][7][8][9]. NF-κB gene polymorphisms influence the susceptibility to type 1 and 2 diabetes and affect microvascular and atherosclerotic complications in patients [13,28,29]. Hyperglycaemia, dyslipidaemia, oxidative stress and inflammation can also lead to the occurrence of diabetes complications by activating canonical NF-κB-driven genes [15].…”

Section: Resultsmentioning

confidence: 99%

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

¹

,

²

,

³

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis.Methods Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.

“…While the allele frequency of NF-κB1A was 34.33% in the controls, it was reported as 36% in China, 37% in a German population, 45% in a Czech population (12) and 29% in an Australian-Jewish population (13). Arslan and Engin (9) reported this allele frequency as 32.3% in a Turkish population.…”

Section: Discussionmentioning

confidence: 99%

Association between NF-κBI and NF-κBIA polymorphisms and coronary artery disease

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et al. 2015

Biomedical Reports

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Abstract. Coronary artery disease (CAD) is the leading cause of fatalities worldwide. Nuclear factor (NF)-κB is a transcription factor that controls cell proliferation, differentiation and immunity. To the best of our knowledge, the present study is the first investigation of the association between CAD and NF-κB1 -94 W/D/NF-κBIA 3'-untranslated region (3'-UTR) A→G polymorphisms. The study population comprised 226 CAD patients and 201 controls. There was no significant difference in NF-κB1A 3'-UTR A→G in the allele and genotype frequencies between case and control populations. The D allele frequency of NF-κB1 -94 in the case group was significantly higher compared to the control group (P=0.028, odds ratio=1.37). The genotype frequency of NF-κB1 -94 DD in the case group was significantly higher compared to the controls (P= 0.028). Linkage analysis showed a close linkage among these 2 genes (P<0.001 for case and control), and AD and GD haplotypes were associated with CAD (P<0.001; P= 0.015, respectively). NF-κB1 -94 DD genotype can be a significant risk factor for the development of CAD.

“…When focusing on the transcription factors that were regulated during hyperinsulinaemia in the control group but not in the insulin-resistant patients, we identified a subset of 30 genes with an impaired response. Interestingly, two of them (ESR1 and NFKBIA) have previously been associated with type 2 diabetes and insulin resistance traits in genetic studies [32,33], and individuals with defective HMGA1 expression showed decreased insulin receptor levels and a diabetic phenotype [34]. Thus, the altered regulation of the expression of these genes by insulin may contribute to the pathology.…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of genes with impaired insulin regulation in the skeletal muscle of type 2 diabetic patients indicates the involvement of basic helix-loop-helix domain-containing, class B, 2 protein (BHLHB2)

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et al. 2009

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Aims/hypothesis One of the major processes by which insulin exerts its multiple biological actions is through gene expression regulation. Thus, the identification of transcription factors affected by insulin in target tissues represents an important challenge. The aim of the present study was to gain a greater insight into this issue through the identification of transcription factor genes with insulinregulated expression in human skeletal muscle. Methods Using microarray analysis, we defined the sets of genes modulated during a 3 h hyperinsulinaemic-euglycaemic clamp (2 mU min −1 kg −1 ) in the skeletal muscle of insulin-sensitive control volunteers and in moderately obese insulin-resistant type 2 diabetic patients.Results Of the 1,529 and 1,499 genes regulated during the clamp in control and diabetic volunteers, respectively, we identified 30 transcription factors with impaired insulinregulation in type 2 diabetic patients. Analysis of the promoters of the genes encoding these factors revealed a possible contribution of the transcriptional repressor basic helix-loop-helix domain-containing, class B, 2 protein (BHLHB2), insulin regulation of which is strongly altered in the muscle of diabetic patients. Gene ontology analysis of BHLHB2 target genes, identified after BHLHB2 overexpression in human primary myotubes, demonstrated that about 10% of the genes regulated in vivo during hyperinsulinaemia are potentially under the control of this repressor. The data also suggested that BHLHB2 is situated at the crossroads of a complex transcriptional network that is able to modulate major metabolic and biological pathways in skeletal muscle, including the regulation of a cluster of genes involved in muscle development and contraction. Conclusions/interpretation We have identified BHLHB2 as a potential novel mediator of insulin transcriptional action in human skeletal muscle.

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