NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats

Müller, Dominik N.; Dechend, Ralf; Mervaala, Eero; Park, Joon-Keun; Schmidt, Folke; Fiebeler, Anette; Theuer, Jürgen; Breu, Volker; Ganten, Detlev; Haller, Hermann; Luft, Friedrich C.

doi:10.1161/01.hyp.35.1.193

Cited by 371 publications

(312 citation statements)

References 56 publications

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“…In addition, altered renal expression of AT1 precedes the development of renal fibrosis in aging rats (Schulman et al 2010). Ang II, an important vascular constrictor, is recognized as a potent pro-inflammatory mediator that participates in vascular inflammatory responses (Ferrario and Strawn 2006;Muller et al 2000;Ruiz-Ortega et al 2000). It seems clear that the production of RS and the activation of transcription factor NF-κB play major roles in the intracellular signaling pathways involved in RAS and Ang II-induced inflammation (Ungvari et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Kim

Heo

et al. 2011

AGE

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Angiotensin II (Ang II), a major effector of the renin-angiotensin system, is now recognized as a pro-inflammatory mediator. This Ang II signaling, which causes transcription of pro-inflammatory genes, is regulated through nuclear factor-κB (NF-κB). At present, the molecular mechanisms underlying the effect of aging on Ang II signaling and NF-κB activation are not fully understood. The purpose of this study was to document altered molecular events involved in agerelated changes in Ang II signaling and NF-κB activation. Experimentations were carried out using kidney tissues from Fischer 344 rats at 6, 12, 18, and 24 months of age, and the rat endothelial cell line, YPEN-1 for the detailed molecular work. Results show that increases in Ang II and Ang II type 1 receptor during aging were accompanied by the generation of reactive species. Increased Ang II activated NF-κB by phosphorylating IκBα and p65. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IκB kinase αβ, while phosphorylation site Ser 276 of p65 was mediated by upregulated mitogen-activated and stress-activated protein kinase-1. These altered molecular events in aged animals were partly verified by experiments using YPEN-1 cells. Collectively, our findings provide molecular insights into the pro-inflammatory actions of Ang II, actions that influence the phosphorylation of p65-mediated NF-κB activation during aging. Our study demonstrates the age-related pleiotropic nature of the physiologically important Ang II can change into a deleterious culprit that contributes to an increased incidence of many chronic diseases such as atherosclerosis, diabetes, and dementia.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Kim

Heo

et al. 2011

AGE

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“…Dechend et al reported that AT 1 -AAs induced signaling in vascular cells including AP-1 and NF-κB activation (10,11). Both of these nuclear factors participate in inflammation (23,24). Wallukat et al found monocytes, which were pivotal to vascular wall inflammatory processes, could be stimulated by AT 1 -AAs to adhere, produce tissue factor, and probably reactive oxygen species (25).…”

Section: Discussionmentioning

confidence: 99%

Agonistic AT1 Receptor Autoantibody Increases in Serum of Patients with Refractory Hypertension and Improves Ca2+ Mobilization in Cultured Rat Vascular Smooth Muscle Cells

et al. 2008

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Agonistic AT 1 receptor autoantibodies (AT 1 -AAs) have been described in the patients with malignant hypertension or preeclampia. Furthermore, AT 1 -AAs were highly associated with refractory hypertension. Function of vascular smooth muscle cells (VSMCs) is important in the regulation of blood pressure. We investigated and compared the ability of angiotensin II (Ang II) and AT 1 -AAs to stimulate the intracellular calcium mobilization and cellular proliferation of rat VSMCs. Twenty-two patients with refractory hypertension, 24 patients with non-refractory hypertension and 37 normotensives were recruited. The serum of each patient was detected for the presence of

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“…49 Previously we have shown that in dTGR, Ang II-mediated leukocyte infiltration and adhesion molecule overexpression are due to Ang II-induced ROS formation and activation of the redox-sensitive transcription factors NF-B and AP-1. 50 Very recently, we showed that Ang II controls the migration of mature dendritic MHC II-positive cells whose maturation process seemed to be controlled by TNF␣. 51 In contrast, blood pressure did not influence the maturation process as the infiltration of immune cells and resultant vascular damage was prevented by dexamethasone without lowering of blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

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102

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Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis.Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGF␤ 1 , collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cellmediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and cal-

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NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats

Abstract: Abstract-We recently reported that the activation of nuclear factor-B (NF-B) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]

Cited by 371 publications

References 56 publications

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Agonistic AT1 Receptor Autoantibody Increases in Serum of Patients with Refractory Hypertension and Improves Ca2+ Mobilization in Cultured Rat Vascular Smooth Muscle Cells

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

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