Angiotensin II and tumor necrosis factor-α synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-κB, p38, and reactive oxygen species

2008 ◽  
Vol 294 (6) ◽  
pp. H2879-H2888 ◽  
Author(s):  
Masao Takahashi ◽  
Etsu Suzuki ◽  
Ryo Takeda ◽  
Shigeyoshi Oba ◽  
Hiroaki Nishimatsu ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Vascular Inflammation ◽  
Ang Ii ◽  
Neointimal Formation ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Tnf Α ◽  
Dependent Pathway

We examined whether ANG II and TNF-α cooperatively induce vascular inflammation using the expression of monocyte chemoattractant protein (MCP)-1 as a marker of vascular inflammation. ANG II and TNF-α stimulated MCP-1 expression in a synergistic manner in vascular smooth muscle cells. ANG II-induced MCP-1 expression was potently inhibited to a nonstimulated basal level by blockade of the p38-dependent pathway but only partially inhibited by blockade of the NF-κB-dependent pathway. In contrast, TNF-α-induced MCP-1 expression was potently suppressed by blockade of NF-κB activation but only modestly suppressed by blockade of p38 activation. ANG II- and TNF-α-induced activation of NF-κB- and p38-dependent pathways was partially inhibited by pharmacological inhibitors of ROS production. Furthermore, ANG II- and TNF-α-stimulated MCP-1 expression was partially suppressed by ROS inhibitors. We also examined whether endogenous ANG II and TNF-α cooperatively promote vascular inflammation in vivo using a wire injury model of the rat femoral artery. Blockade of both ANG II and TNF-α further suppressed neointimal formation, macrophage infiltration, and MCP-1 expression in an additive manner compared with blockade of ANG II or TNF-α alone. These results suggested that ANG II and TNF-α synergistically stimulate MCP-1 expression via the utilization of distinct intracellular signaling pathways (p38- and NFκB-dependent pathways) and that these pathways are activated in ROS-dependent and -independent manners. These results also suggest that ANG II and TNF-α cooperatively stimulate vascular inflammation in vivo as well as in vitro.

Angiotensin II induces monocyte chemoattractant protein-1 expression via a nuclear factor-κB-dependent pathway in rat preadipocytes

2006 ◽  
Vol 291 (4) ◽  
pp. E771-E778 ◽  
Author(s):  
Kyoichiro Tsuchiya ◽  
Takanobu Yoshimoto ◽  
Yuki Hirono ◽  
Toru Tateno ◽  
Toru Sugiyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Luciferase Assay ◽  
Ang Ii ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Dependent Pathway

Both monocyte chemoattractant protein-1 (MCP-1), a member of chemokine family, and angiotensinogen, a precursor of angiotensin (ANG) II, are produced by adipose tissue and increased in obese state. MCP-1 has been shown to decrease insulin-stimulated glucose uptake and several adipogenic genes expression in adipocytes in vitro, suggesting its pathophysiological significance in obesity. However, the pathophysiological interaction between MCP-1 and ANG II in adipose tissue remains unknown. The present study was undertaken to investigate the potential mechanisms by which ANG II affects MCP-1 gene expression in rat primary cultured preadipocytes and adipose tissue in vivo. ANG II significantly increased steady-state MCP-1 mRNA levels in a time- and dose-dependent manner. The ANG II-induced MCP-1 mRNA and protein expression was completely abolished by ANG II type 1 (AT1)-receptor antagonist (valsartan). An antioxidant/NF-κB inhibitor (pyrrolidine dithiocarbamate) and an inhibitor of 1κB-α phosphorylation (Bay 11-7085) also blocked ANG II-induced MCP-1 mRNA expression. ANG II induced translocation of NF-κB p65 subunit from cytoplasm to nucleus by immunocytochemical study. Luciferase assay using reporter constructs containing MCP-1 promoter region revealed that two NF-κB binding sites in its enhancer region were essential for the ANG II-induced promoter activities. Furthermore, basal mRNA and protein of MCP-1 during preadipocyte differentiation were significantly greater in preadipocytes than in differentiated adipocytes, whose effect was more pronounced in the presence of ANG II. Exogenous administration of ANG II to rats led to increased MCP-1 expression in epididymal, subcutaneous, and mesenteric adipose tissue. In conclusion, our present study demonstrates that ANG II increases MCP-1 gene expression via ANG II type 1 receptor-mediated and NF-κB-dependent pathway in rat preadipocytes as well as adipose MCP-1 expression in vivo. Thus the augmented MCP-1 expression by ANG II in preadipocytes may provide a new link between obesity and cardiovascular disease.

scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

scholarly journals Peroxisome Proliferator-Activated ReceptorαPlays an Important Role in the Expression of Monocyte Chemoattractant Protein-1 and Neointimal Hyperplasia after Vascular Injury

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Yu Peng ◽  
Qiang Li ◽  
Lu Zhang ◽  
Ming Bai ◽  
Zheng Zhang
Keyword(s):  
Carotid Artery ◽  
Neointimal Hyperplasia ◽  
Peroxisome Proliferator ◽  
Neointimal Formation ◽  
Carotid Artery Injury ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Artery Injury

Peroxisome proliferator-activated receptorαis a member of the nuclear receptor superfamily. It modulates smooth muscle cell proliferation and inflammatory cytokines in vitro. In this study, we tested the hypothesis that PPARαwould decrease the expression of monocyte chemoattractant protein-1 and tissue factor, and inhibit neointimal formation in a murine double carotid artery injury model. Carotid artery injury was performed in the PPARαknockout and wild type (WT) mice, treated and untreated with Wy14643, a PPARαactivator. Up-regulated MCP-1 and TF expression and more neointimal formation were observed in the PPARα−/−mice compared with WT mice. The activation of PPARαresulted in further decreased neointimal formation. Our data further suggest that the decrease in neointimal formation is due to down-regulation of MCP-1 by PPARαresulting in decreased leukocyte infiltration and TF expression.

Ultrasonicated Lespedeza cuneata extract prevents TNF-α-induced early atherosclerosis in vitro and in vivo

2018 ◽  
Vol 9 (4) ◽  
pp. 2090-2101 ◽  
Author(s):  
Su Jeong Ha ◽  
Jangho Lee ◽  
Kyung-Mo Song ◽  
Young Ho Kim ◽  
Nam Hyouck Lee ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Lespedeza Cuneata ◽  
Tnf Α ◽  
Early Atherosclerosis

This study evaluated the use of ultrasonication to extract Lespedeza cuneata as a potential nutraceutical for preventing vascular inflammation.

scholarly journals Monocyte Chemoattractant Protein-1 stimulates the differentiation of rat stem and progenitor Leydig cells during regeneration

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiangcheng Zhan ◽  
Jingwei Zhang ◽  
Saiyang Li ◽  
Xiaolu Zhang ◽  
Linchao Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Monocyte Chemoattractant Protein 1 ◽  
Rat Testis ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein

Abstract Background Monocyte chemoattractant protein-1(MCP-1) is a chemokine secreted by Leydig cells and peritubular myoid cells in the rat testis. Its role in regulating the development of Leydig cells via autocrine and paracrine is still unclear. The objective of the current study was to investigate the effects of MCP-1 on Leydig cell regeneration from stem cells in vivo and on Leydig cell development in vitro. Results Intratesticular injection of MCP-1(10 ng/testis) into Leydig cell-depleted rat testis from post-EDS day 14 to 28 significantly increased serum testosterone and luteinizing hormone levels, up-regulated the expression of Leydig cell proteins, LHCGR, SCARB1, CYP11A1, HSD3B1, CYP17A1, and HSD17B3 without affecting progenitor Leydig cell proliferation, as well as increased ERK1/2 phosphorylation. MCP-1 (100 ng/ml) significantly increased medium testosterone levels and up-regulated LHCGR, CYP11A1, and HSD3B1 expression without affecting EdU incorporation into stem cells after in vitro culture for 7 days. RS102895, a CCR2 inhibitor, reversed MCP-1-mediated increase of testosterone level after culture in combination with MCP-1. Conclusion MCP-1 stimulates the differentiation of stem and progenitor Leydig cells without affecting their proliferation.

scholarly journals An evaluation of the antioxidant protein α1-microglobulin as a renal tubular cytoprotectant

2016 ◽  
Vol 311 (3) ◽  
pp. F640-F651 ◽  
Author(s):  
Richard A. Zager ◽  
Ali C. M. Johnson ◽  
Kirsten Frostad
Keyword(s):  
Proximal Tubule ◽  
Proximal Tubules ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Monocyte Chemoattractant Protein ◽  
Antioxidant Protein ◽  
Neutrophil Gelatinase

α1-Microglobulin (A1M) is a low-molecular-weight heme-binding antioxidant protein that is readily filtered by the glomerulus and reabsorbed by proximal tubules. Given these properties, recombinant A1M (rA1M) has been proposed as a renal antioxidant and therapeutic agent. However, little direct evidence to support this hypothesis exists. Hence, we have sought “proof of concept” in this regard. Cultured proximal tubule (HK-2) cells or isolated mouse proximal tubule segments were challenged with a variety of prooxidant insults: 1) hemin, 2) myoglobin; 3) “catalytic” iron, 4) H2O2/Fenton reagents, 5) a Ca2+ ionophore, 6) antimycin A, or 7) hypoxia (with or without rA1M treatment). HK-2 injury was gauged by the percent lactate dehydrogenase release and 4,5-(dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide uptake. In vivo protection was sought in rA1M-treated mice subjected to 1) graded myohemoglobinura (2, 4, 8, or 9 ml/kg glycerol injection), 2) purified myoglobinemia/uria, or 3) endotoxemia. In vivo injury was assessed by blood urea nitrogen, creatinine, and the expression of redox-sensitive genes (heme oxygenase-1, neutrophil gelatinase-associated lipocalin, and monocyte chemoattractant protein-1 mRNAs). Although rA1M totally blocked in vitro hemin toxicity, equimolar albumin (another heme binder) or 10% serum induced equal protection. rA1M failed to mitigate any nonhemin forms of either in vitro or in vivo injury. A1M appeared to be rapidly degraded within proximal tubules (by Western blot analysis). Surprisingly, rA1M exerted select injury-promoting effects (increased in vitro catalytic iron/antimycin toxicities and increased in vivo monocyte chemoattractant protein-1/neutrophil gelatinase-associated lipocalin mRNA expression after glycerol or endotoxin injection). We conclude that rA1M has questionable utility as a renal antioxidant/cytoprotective agent, particularly in the presence of larger amounts of competitive free heme (e.g., albumin) binders.

scholarly journals An Antagonist of Monocyte Chemoattractant Protein 1 (MCP-1) Inhibits Arthritis in the MRL-lpr Mouse Model

1997 ◽  
Vol 186 (1) ◽  
pp. 131-137 ◽  
Author(s):  
Jiang-Hong Gong ◽  
Leslie G. Ratkay ◽  
J. Douglas Waterfield ◽  
Ian Clark-Lewis
Keyword(s):  
Mouse Model ◽  
Competitive Inhibition ◽  
Human Monocyte ◽  
Daily Injection ◽  
Human Rheumatoid Arthritis ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein

An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

Apoptotic myocytes generate monocyte chemoattractant protein-1 and mediate macrophage recruitment

2008 ◽  
Vol 104 (3) ◽  
pp. 601-609 ◽  
Author(s):  
Miyuki Kobara ◽  
Nahoko Sunagawa ◽  
Masaki Abe ◽  
Nana Tanaka ◽  
Hiroe Toba ◽  
...  
Keyword(s):  
Critical Role ◽  
Neonatal Rat ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Nuclear Staining ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Protein Levels ◽  
Monocyte Chemoattractant Protein

The mechanisms by which apoptotic myocytes are removed by macrophages have not been fully elucidated. This study examined whether apoptotic myocytes actively recruit macrophages by generating monocyte chemoattractant protein-1 (MCP-1) in experiments in vitro and in vivo. Neonatal rat cardiac myocytes were incubated for 4 h in the presence or absence of staurosporine (STS, 0.2–1 μmol/l), an apoptosis inducer. Nuclear staining with DAPI showed that STS induced apoptosis in a dose-dependent fashion. STS (1 μmol/l) caused extensive DNA fragmentation and increased caspase-3 activity compared with a serum-deprived control. MCP-1 mRNA and protein levels in myocytes increased twofold and fourfold, respectively, on STS treatment, and immunochemical staining revealed that apoptotic myocytes expressed MCP-1. To elucidate the role of MCP-1 expressed in apoptotic myocytes to recruit macrophages/monocytes, rat monocytes were incubated in the supernatant of STS-treated myocytes using a trans-well system. The culture medium of STS-treated myocytes recruited monocytes in a MCP-1-dependent fashion. In addition, experiments were performed in vivo using ischemia-reperfused rat hearts. Rats were subjected to 30 min of ligation of the left coronary artery followed by 24 h of reperfusion. After the reperfusion, in the ischemic border myocardium, 17.1 ± 1.1% of myocytes were terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) positive. Moreover, double staining using the TUNEL technique and immunohistochemistry with MCP-1 antibody showed that 69.8 ± 3.9% of TUNEL-positive myocytes expressed MCP-1 protein. Concomitantly, activated macrophages infiltrated the areas of apoptosis remarkably. These results suggest that apoptotic myocytes produce MCP-1, which have a critical role in the active recruitment of macrophages.

scholarly journals Angiotensin II enhances the increase in monocyte chemoattractant protein-1 production induced by tumor necrosis factor-α from 3T3-L1 preadipocytes

2009 ◽  
Vol 202 (2) ◽  
pp. 199-205 ◽  
Author(s):  
Sachie Asamizu ◽  
Masaharu Urakaze ◽  
Chikaaki Kobashi ◽  
Manabu Ishiki ◽  
Amal Khalifa Norel Din ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Ang Ii ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) in adipose tissue are thought to induce systemic insulin resistance in rodents; but the precise mechanism is not fully clarified. We examined the mechanism of Ang II-induced and/or tumor necrosis factor-α (TNF-α)-induced MCP-1 production from 3T3-L1 preadipocytes. The MCP-1 protein and MCP-1 mRNA expression in 3T3-L1 preadipocytes were increased significantly by stimulation with TNF-α. We found no significant increase in MCP-1 concentrations by Ang II alone; but it enhanced the TNF-α-induced MCP-1 mRNA expression in a dose-dependent manner. Then, we examined the effect of Ang II and/or TNF-α on phosphorylation of extracellular signal-regulated kinase (ERK), p38MAPK, and IκB-α. Ang II and TNF-α clearly enhanced ERK and p38MAPK phosphorylation. IκB-α phosphorylation was enhanced by TNF-α, but not by Ang II. The MCP-1 mRNA expression induced by TNF-α and co-stimulation with Ang II was inhibited by either ERK inhibitor, p38MAPK inhibitor or NF-κB inhibitor. Moreover, Ang II enhanced the activation of AP-1 (c-fos) induced by TNF-α. Our results suggest that Ang II may serve as an additional stimulus on the TNF-α-induced MCP-1 production through the ERK-and p38MAPK-dependent pathways probably due to AP-1 activation.

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