Lovastatin inhibits lipopolysaccharide-induced NF-kB activation in human mesangial cells

Guijarro, C.; Kim, Y.; Schoonover, C. M.; Massy, Ziad A.; O’Donnell, Micheal P.; Kasiske, Bertram L.; Keane, William F.; Kashtan, Clifford E.

doi:10.1093/oxfordjournals.ndt.a027522

Cited by 54 publications

(18 citation statements)

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“…It was also revealed that increased NF-κB activation in mesangial cells correlates with increased expression of a variety of inflammatory genes such as interleukins IL-1β IL-6 and IL-8, tumor necrosis factor α (TNF-α) monocyte chemoattractant protein-1 (MCP-1), interferon invasive protein-10 (IP-10), and inducible nitric oxide synthase [2,10,[19][20][21][22][23]. In addition to the proinflammatory actions of NF-κB, some data, similarly as our study, support a role for NF-κB in the control of mesangial cell proliferation [2,[24][25][26][27][28].…”

Section: Discussionsupporting

confidence: 74%

The immunoexpression of glomerular NF-κB in proteinuric patients with proliferative and non-proliferative glomerulopathies

Danilewicz¹,

Wągrowska-Danilewicz²

2013

pjp

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Recent studies suggest that NF-κB activation plays an essential role in the activation of mesangial cells and macrophages through the transcriptional induction of inflammatory mediators of glomerular inflammation and injury. The aim of the present study was to determine, using an image analysis system, glomerular immunoexpression of NF-κB (nuclear translocation of p65) in proteinuric patients with proliferative and non-proliferative glomerulopathies. Thirty-six proteinuric patients with idiopathic proliferative glomerulopathies (PG group) and 28 proteinuric participants with non-proliferative glomerulopathies (NPG group) were examined by percutaneous renal biopsy. As a control 12 biopsy specimens of the kidneys removed because of trauma were used. In the PG group the mean values of the glomerular immunoexpression of NF-κB were significantly increased as compared to both NPG patients and controls. In the PG but not in the MPG group glomerular immunoexpression of NF-κB was significantly positively correlated with the degree of proteinuria. Moreover, in the PG group glomerular immunoexpression of NF-κB was positively correlated with the mesangial cells, mesangial area and glomerular monocytes/macrophages. In conclusion, our results strongly suggest a role of NF-κB in glomerular injury in proteinuric patients with proliferative glomerulopathies.

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Section: Discussionsupporting

confidence: 74%

The immunoexpression of glomerular NF-κB in proteinuric patients with proliferative and non-proliferative glomerulopathies

Danilewicz¹,

Wągrowska-Danilewicz²

2013

pjp

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“…There is now evidence to support the view that besides having a major lipid-lowering effect, statins also have an antiinflammatory effect, 39 probably acting through modulation of NF--B activity. 40,41 Thus, part of the reduced influence of the stromelysin genotype on disease progression in treated Mean (95% CI) IMT of carotid bifurcation according to combined genotype of stromelysin-1 5A/6A and IL-6 G/C polymorphisms; 5 and 6 refer to 5A and 6A alleles of stromelysin-1 polymorphism; C and G refer to IL-6 alleles. Adjusted for age, cardiorespiratory fitness, body mass index, smoking, LDL cholesterol, and systolic blood pressure and for sonographers.…”

Section: Discussionmentioning

confidence: 99%

Stromelysin-1 and Interleukin-6 Gene Promoter Polymorphisms Are Determinants of Asymptomatic Carotid Artery Atherosclerosis

Rauramaa

Väisänen²,

Luong³

et al. 2000

ATVB

193

109

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Abstract-The functional 5A/6A polymorphism of the stromelysin-1 promoter has been implicated as a potential genetic marker for the progression of angiographically determined atherosclerosis in patients with coronary artery disease. Recently, a novel interleukin-6 (IL-6) gene functional G/C polymorphism at Ϫ174 in the promoter has also been reported. In this study, we analyzed the relation of these two polymorphisms with carotid artery atherosclerosis in 109 randomly selected, middle-aged men without exercise-induced ischemia. Atherosclerosis was quantified as intimamedia thickness (IMT) by high-resolution ultrasonography. Univariately, stromelysin genotype was significantly (Pϭ0.015) associated with IMT, and this relation remained (Pϭ0.033) after adjustments for age, cardiorespiratory fitness, body mass index, smoking, LDL cholesterol, and systolic blood pressure and for sonographers. The 5A/6A polymorphism independently explained 7% of the variance in carotid bifurcation IMT. The IL-6 polymorphism was also significantly associated (Pϭ0.036) with increased IMT, with men homozygous for the G allele having IMT that was 11% greater than men homozygous for the C allele. Men who were homozygous for both the 6A and G alleles had an covariate adjusted IMT that was 36% greater than men who were homozygous for neither allele (PϽ0.003). These data suggest that genetic factors that predispose to reduced matrix remodeling (stromelysin 6A allele) and to increased inflammation (IL-6 G allele) combine to increase susceptibility for intima-media thickening in the carotid bifurcation, a predilection site for atherosclerosis. Key Words: stromelysin-1 Ⅲ interleukin-6 Ⅲ DNA polymorphism Ⅲ B-mode ultrasonography Ⅲ carotid atherosclerosis Ⅲ population sample

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“…24 Decreased NF-B activity in mesangial cells has been detected on treatment with lovastatin, 25 whereas simvastatin has been found to increase NF-B activation in endothelial cells. 26 Our investigations, being the first to use transient transfection techniques and to compare different statins at various concentrations, clearly support the notion that HMG-CoA reductase inhibitors curtail NF-B signaling.…”

Section: Dichtl Et Al Statins and Transcription Factorsmentioning

confidence: 99%

HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells

Dichtl

Dulak

Frick

et al. 2003

ATVB

316

197

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Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-B) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay ( Key Words: statins Ⅲ nuclear factor-B Ⅲ activator protein-1 Ⅲ hypoxia-inducible factor-1␣ Ⅲ vascular endothelial growth factor R andomized clinical trials have clearly shown the benefit of statin therapy in the reduction of cardiovascular events and total mortality in coronary heart disease patients with either high or normal cholesterol levels. 1 In these studies, survival curves began to diverge within a relatively short period of time and before effects on plaque size were likely to occur. Demonstrated effects of HMG-CoA reductase inhibitors were not reflected by a regression in coronary stenoses as assessed by angiography. These findings have suggested that mechanisms of statins beyond lipid lowering are likely to be involved in the reduction of coronary events. 2 Both in vivo and in vitro studies support the notion that statins counteract the chronic subclinical vascular inflammatory state associated with atherosclerosis. 3,4 Statins inhibit leukocyte-endothelium interaction 5-7 and decrease inflammation in carotid lesions in humans. 8 Many of the vasculoprotective effects of HMG-CoA reductase inhibitors seem to be mediated by enhanced availability of nitric oxide. 9 There is increasing evidence that statins may act on the transcriptional level as well, eg, simvastatin inhibited endothelial secretion of PAI-1, which was correlated with reduced mRNA transcription and activity of the promoter. 10 Despite extensive research on molecular mechanisms of statins, little is known about the interactions of these drugs with transcription factors. The aim of this study was to characterize the effects of simvastatin, atorvastatin, and lovastatin on the activation of nuclear factor (NF)-B, activator protein (AP)-1, and hypoxia-inducible factor (HIF)-1␣ in endothelial and arterial smooth muscle cells. Because these factors regulate the transcription of many genes, including cytokines, chemokines, adhesion molecules, and growth factors, such interactions of statins on vascular cell signaling and gene expression may explain atheroprotective effects not directly related to cholesterol lowering. MethodsSimvastatin (MSD) and lovastatin (Calbiochem) prodrugs were activated from their inactive lactone proforms to their active dihy-

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Lovastatin inhibits lipopolysaccharide-induced NF-kB activation in human mesangial cells

Abstract: These data suggest an additional mechanism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-kappaB activation and the subsequent proliferative and inflammatory responses.

Cited by 54 publications

References 0 publications

The immunoexpression of glomerular NF-κB in proteinuric patients with proliferative and non-proliferative glomerulopathies

The immunoexpression of glomerular NF-κB in proteinuric patients with proliferative and non-proliferative glomerulopathies

Stromelysin-1 and Interleukin-6 Gene Promoter Polymorphisms Are Determinants of Asymptomatic Carotid Artery Atherosclerosis

HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells

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