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Yusuke Suzuki

Publications and source records attributed to Yusuke Suzuki.

At least 73 records · Page 4Linked to original sources
PubMed2003

Inflammation and angiotensin II.

Angiotensin II (AngII), the major effector peptide of renin-angiotensin system (RAS), is now recognized as a growth factor that regulates cell growth and fibrosis, besides being a physiological mediator restoring circulatory integrity. In the last few years, a large number of experimental studies has further demonstrated that AngII is involved in key events of the inflammatory process. Here, we summarize the wide variety of AngII functions and discuss them in relation with the inflammatory cascade. AngII increases vascular permeability (via the release of prostaglandins and vascular endothelial cell growth factor or rearrangement of cytoskeletal proteins) that initiates the inflammatory process. AngII could contribute to the recruitment of inflammatory cells into the tissue through the regulation of adhesion molecules and chemokines by resident cells. Moreover, AngII could directly activate infiltrating immunocompetent cells, including chemotaxis, differentiation and proliferation. Recent data also suggest that RAS activation could play a certain role even in immunologically-induced inflammation. Transcriptional regulation, predominantly via nuclear factor-kappaB (NF-kappaB) and AP-1 activation, and second mediator systems, such as endothelin-1, the small G protein (Rho) and redox-pathways are shown to be involved in the molecular mechanism by which AngII exerts those functions. Finally, AngII participates in tissue repair and remodeling, through the regulation of cell growth and matrix synthesis. In summary, recent data support the hypothesis that RAS is key mediator of inflammation. Further understanding of the role of the RAS in this process may provide important opportunities for clinical research and treatment of inflammatory diseases.

Angiotensin II↗
PubMed2003

Renal expression of angiotensin type 2 (AT2) receptors during kidney damage.

BACKGROUND: Activation of the renin angiotensin system has been described in pathologic conditions, including kidney damage. Angiotensin II (Ang II) acts through two receptors, AT1 and AT2. Most of the known actions of Ang II, including vasoconstriction and fibrosis, are due to AT1 activation. Recent data suggest that AT2 participates in the regulation of cell growth and renal inflammatory infiltration. Therefore, we investigated the renal expression of AT2 receptors in several models of renal injury. METHODS: Investigations were done in the following experimental models of kidney damage: systemic infusion of Ang II (inflammation), folic acid nephropathy (tubular cell death), and protein overload proteinuria. AT2 expression was determined by immunohistochemistry (protein) and reverse transcription-polymerase chain reaction (RT-PCR) (gene). RESULTS: In control animals, low levels of renal expression of AT2 were found. Ang II infusion resulted in an up-regulation of AT2 in tubular cells and de novo AT2 expression in glomeruli and vessels, associated with the presence of inflammatory cells. Acute tubular injury induced by folic acid was characterized by AT2 overexpression and apoptosis in tubular cells. Protein overload caused heavy proteinuria and tubular AT2 up-regulation. CONCLUSION: AT2 is re-expressed in pathologic conditions of kidney damage, such as inflammation, apoptosis, and proteinuria, suggesting a potential role of this receptor during renal injury.

Angiotensin II↗
PubMed2003

Different glial reactions to hippocampal stab wounds in young adult and aged rats.

Brain injury induces reactive gliosis. To examine the activation of glial cells after brain injury in young versus aged rats, we used a brain stab-wound model and examined the expression of cells positive for ED1 (ED1(+)) and glial fibrillary acidic protein (GFAP(+)) in the hippocampus in young-mature (3 months) and aged (25 months) Wistar rats at various times following hippocampal stab injury. ED1(+) cells appeared more frequently in the aged rats than in the young-mature rats under control conditions, whereas the number of GFAP(+) cells was not different between two groups. Following the stab wound, there was an increase in ED1 expression that was delayed but stronger in the aged rats and that persisted longer; the increase of the number of GFAP(+) cells also persisted longer. We conclude that different glial reactivity in the aged brain suggests that aging is associated with increased glial responsiveness that may enhance susceptibility to injury and disease in the brain.

Age Factors↗
PubMed2003

Impaired olfactory identification in Asperger's syndrome.

The authors measured odor detection threshold and odor identification in 12 males with Asperger's syndrome and 12 matched control subjects. Relative to control subjects, Asperger's syndrome subjects were not impaired at odor detection but were significantly impaired at olfactory identification.

Adult↗
PubMed2003

Plasma adiponectin plays an important role in improving insulin resistance with glimepiride in elderly type 2 diabetic subjects.

OBJECTIVE: We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2alpha (8-epi-PGF2alpha), an oxidative stress marker. RESEARCH DESIGN AND METHODS: A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA(1c), C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS: After 8 weeks of glimepiride treatment, significant reductions were observed in HbA(1c) (from 8.4 +/- 1.9 to 6.9 +/- 1.0%), HOMA-IR (from 2.54 +/- 2.25 to 1.69 +/- 0.95%), and plasma TNF-alpha concentrations (from 4.0 +/- 2.0 to 2.6 +/- 2.5 pg/ml). MCR-g was significantly increased from 3.92 +/- 1.09 to 5.73 +/- 1.47 mg. kg(-1). min(-1). Plasma adiponectin increased from 6.61 +/- 3.06 to 10.2 +/- 7.14 micro g/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS: Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA(1c) without changing extrapancreatic beta-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride.

Adiponectin↗
PubMed2002

Role of endogenous vascular endothelial growth factor in tubular cell protection against acute cyclosporine toxicity.

BACKGROUND: Recent studies have shown that exogenous administration of vascular endothelial growth factor (VEGF) is protective against cyclosporine A (CsA) renal toxicity. No data are available, however, on the possible role of endogenous VEGF. Our objective was to examine whether endogenous VEGF has a significant role in the renal response against CsA toxicity. METHODS: In vivo, we used high-dose (50-150 mg/kg/day) CsA +/- specific goat anti-mouse VEGF blocking monoclonal antibody (alpha-VEGF) in mice. In vitro, we exposed mouse tubular cells (MCT) to CsA +/- alpha-VEGF. RESULTS: alpha-VEGF markedly enhanced CsA renal toxicity, inducing severe tubular damage and increased blood urea nitrogen. In animals treated with CsA + alpha-VEGF, damage progressed to generalized tubular injury (histology) and apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling) with associated anemia and reticulocytosis (18 days of treatment). CsA + alpha-VEGF treatments strikingly increased tubular VEGF and Bcl-xL proteins. In vitro, autocrine production of VEGF by MCT was identified by Western blot. Of specific interest, CsA toxicity in MCT increased significantly in the presence of alpha-VEGF. CONCLUSIONS: Endogenous VEGF has a relevant role in the renal tubular defense against CsA toxicity. Blockade of the VEGF effect by alpha-VEGF results in clear-cut intensification of the tubular injury and appearance of regenerative anemia in the CsA + alpha-VEGF-treated animals. The occurrence of both in vivo and in vitro effects of VEGF blockade provides evidence of a direct protective effect of VEGF on the tubular cell.

Acute Disease↗
PubMed2002

Susceptibility to T cell-mediated injury in immune complex disease is linked to local activation of renin-angiotensin system: the role of NF-AT pathway.

FcR provides a critical link between ligands and effector cells in immune complex diseases. Emerging evidence reveals that angiotensin (Ang)II exerts a wide variety of cellular effects and contributes to the pathogenesis of inflammatory diseases. In anti-glomerular basement membrane Ab-induced glomerulonephritis (GN), we have previously noted that FcR-deficient mice (gamma(-/-)) surviving from lethal initial damage still developed mesangial proliferative GN, which was drastically prevented by an AngII type 1 receptor (AT1) blocker. We further examined the mechanisms by which renin-Ang system (RAS) participates in this immune disease. Using bone marrow chimeras between gamma(-/-) and AT1(-/-) mice, we found that glomerular injury in gamma(-/-) mice was associated with CD4(+) T cell infiltration depending on renal AT1-stimulation. Based on findings in cutaneous delayed-type hypersensitivity, we showed that AngII-activated renal resident cells are responsible for the recruitment of effector T cells. We next examined the chemotactic activity of AngII-stimulated mesangial cells, as potential mechanisms coupling RAS and cellular immunity. Chemotactic activity for T cells and Th1-associated chemokine (IFN-gamma-inducible protein-10 and macrophage-inflammatory protein 1alpha) expression was markedly reduced in mesangial cells from AT1(-/-) mice. Moreover, this activity was mainly through calcineurin-dependent NF-AT. Although IFN-gamma-inducible protein-10 was NF-kappaB-dependent, macrophage-inflammatory protein 1alpha was dominantly regulated by NF-AT. Furthermore, AT1-dependent NF-AT activation was observed in injured glomeruli by Southwestern histochemistry. In conclusion, our data indicate that local RAS activation, partly via the local NF-AT pathway, enhances the susceptibility to T cell-mediated injury in anti-glomerular basement membrane Ab-induced GN. This novel mechanism affords a rationale for the use of drugs interfering with RAS in immune renal diseases.

Angiotensin II↗
PubMed2002

Cyclooxygenase-2 expression during allergic inflammation in guinea-pig lungs.

Prostaglandins and thromboxanes are important modulators of airway physiology. The synthesis of these mediators depends on two isoforms of cyclooxygenase (COX), constitutive COX-1 and inducible COX-2. COX-2 expression has been observed in various inflammatory diseases, but not all aspects of the expression and the role of COX-2 in conditions of allergic inflammation such as asthma are clear. In the present study, we examined the 72-h kinetics of the expression of COX-isoform mRNA in ovalbumin-sensitized and -challenged guinea-pig lungs. The sensitized animals showed a robust and transient induction of COX-2 mRNA expression within 1 h after ovalbumin challenge, whereas their COX-1 mRNA levels remained unchanged. Upregulation of the level and activity of COX-2 protein followed the induction of COX-2 mRNA. Lung slices harvested from ovalbumin-challenged animals released more prostaglandin D(2) and prostaglandin E(2) spontaneously or in response to A23187 (10 microM) ex vivo than did those from unchallenged animals. This response was significantly blocked by the COX-2 selective inhibitors, NS-398 and JTE-522. In vivo administration of NS-398 significantly inhibited the accumulation of eosinophils and neutrophils in the lungs. In conclusion, de novo COX-2 expression during allergic inflammation modifies prostanoid synthesis in the lung and airway pathophysiology.

Animals↗
PubMed2002

Bone marrow-derived regenerated cardiomyocytes (CMG Cells) express functional adrenergic and muscarinic receptors.

BACKGROUND: We recently reported that cardiomyocytes could be differentiated from bone marrow mesenchymal stem cells in vitro by 5-azacytidine treatment. In native cardiomyocytes, adrenergic and muscarinic receptors play crucial roles in mediating heart rate, conduction velocity, contractility, and cardiac hypertrophy. We investigated whether these receptors are expressed in differentiated CMG cells, and if so, whether they have downstream signaling systems. METHODS AND RESULTS: Reverse transcription-polymerase chain reaction revealed that CMG cells had already expressed alpha(1A)-, alpha(1B)-, and alpha(1D)-adrenergic receptor mRNA before 5-azacytidine treatment, whereas expression of beta(1)-, beta(2)-adrenergic and M(1)-, M(2)-muscarinic receptors was first detected at 1 day. Phenylephrine dose-dependently induced phosphorylation of ERK1/2, which was completely inhibited by prazosin, and significantly increased cell size. Isoproterenol augmented cAMP by 38-fold, which was fully inhibited by propranolol. Isoproterenol (10(-7) mol/L) increased the spontaneous beating rate by 47.6% (basal, 127+/-16 bpm), and propranolol and CGP20712A (beta(1)-selective blocker) reduced it by 79.0% and 71.0%, respectively, whereas ICI118551 (beta(2)-selective blocker) induced slight reduction. Cell motion, percent shortening, and contractile velocity were increased by 37.5%, 26.9%, and 50.6%, respectively, in response to isoproterenol. Phenylephrine and isoproterenol augmented ANP and BNP gene expressions. Carbachol increased IP(3) by 32-fold, which was markedly inhibited by atropine as well as AFDX116 (M(2)-selective blocker) measured by radioimmunoassay. CONCLUSIONS: These findings indicate that CMG cells expressed alpha(1A), alpha(1B), and alpha(1D) receptors before differentiation and expressed beta(1), beta(2), M(1), and M(2) receptors after they obtained the cardiomyocyte phenotype. These receptors had functional signal transduction pathways and could modulate cell function.

Adrenergic alpha-Agonists↗
PubMed2002

Cardiomyogenic differentiation in cardiac myxoma expressing lineage-specific transcription factors.

We investigated five cases of cardiac myxoma and one case of cardiac undifferentiated sarcoma by light and electron microscopy, in situ hybridization, immunohistochemical staining, and reverse transcriptase-polymerase chain reaction for cardiomyocyte-specific transcription factors, Nkx2.5/Csx, GATA-4, MEF2, and eHAND. Conventional light microscopy revealed that cardiac myxoma and sarcoma cells presented variable cellular arrangements and different histological characteristics. Ultrastructurally, some of the myxoma cells exhibited endothelium-like or immature mesenchymal cell differentiation. Immunohistochemistry for Nkx2.5/Csx, GATA-4, and eHAND was slightly to intensely positive in all myxoma cases. MEF2 immunoreactivity was observed in all cases including the case of sarcoma, thus suggesting myogenic differentiation of myxoma or sarcoma cells. In situ hybridization for Nkx2.5/Csx also revealed that all myxoma cells, but not sarcoma cells, expressed mRNA of the cardiac homeobox gene, Nkx2.5/Csx. Furthermore, nested reverse transcriptase-polymerase chain reaction from formalin-fixed, paraffin-embedded tissue was performed and demonstrated that the Nkx2.5/Csx and eHAND gene product to be detected in all cases, and in three of six cases, respectively. In conclusion, cardiac myxoma cells were found to express various amounts of cardiomyocyte-specific transcription factor gene products at the mRNA and protein levels, thus suggesting cardiomyogenic differentiation. These results support the concept that cardiac myxoma might arise from mesenchymal cardiomyocyte progenitor cells.

Aged↗
PubMed2002

Nuclear factor-kappa B inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis.

Nuclear factor (NF)-kappa B regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. In the anti-Thy 1.1 rat model, gliotoxin (75 micro g/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 micro g/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappa B activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. In cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-kappa B activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines, by blocking the phosphorylation/degradation of the I kappa B(alpha) subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappa B activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.

Animals↗
PubMed2002

Nitric oxide production in renal cells by immune complexes: Role of kinases and nuclear factor-kappaB.

BACKGROUND: Interaction of deposited immune complexes (IC) with Fc receptors (FcR) on tissue cells elicits the release of inflammatory mediators leading to tissue damage. Nitric oxide (NO) radicals generated by inducible NO synthase (iNOS) are important mediators in inflammatory processes. To analyze the role of NO in IC-mediated glomerular inflammation, we studied the in vitro and in vivo expression of iNOS in renal cells [resident mesangial cells (MC), and infiltrating monocytes] induced by IC, and the possible intermediate steps between FcR occupancy and iNOS induction. METHODS: MC and monocytes were stimulated with IgG- and IgA-containing IC, and NO production (nitrite accumulation), iNOS transcription (luciferase assay) and their expression was measured by RT-PCR and Western blot. The involvement of FcR, transcription factor nuclear factor-kappaB (NF-kappaB), and protein kinases was assessed by using Fc fragments and specific inhibitors. Immune glomerulonephritis was induced in rats, and iNOS expression and NF-kappaB activation were analyzed. RESULTS: In MC and monocytes, IC enhanced iNOS transcription/expression and NO generation, which were attenuated by specific inhibitors of NF-kappaB. In addition, mitogen-activated protein kinase (MAPK) inhibitors decreased NO production, but did not interfere with NF-kappaB activity, suggesting that both pathways may converge downstream in the induction of iNOS. In experimental immune glomerulonephritis, increased iNOS expression correlated with proteinuria levels, and appeared colocalized with NF-kappaB in glomerular and infiltrating cells. Treatment of animals and cells with Fc fragments prevented iNOS induction and NF-kappaB activation by IC. CONCLUSIONS: These results indicate that IC, through activation of FcR, induce iNOS expression in renal resident and recruited cells by mechanisms involving MAPK and NF-kappaB, and support the idea of the important role of local NO generation in IC-mediated glomerular injury.

Animals↗
PubMed2002

Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.

CysLT(1) antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT(1) antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C(4) synthase (LTC(4) S) gene in Japanese patients with moderate asthma. The frequency of LTC(4) S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects ( n= 349). A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 microg/day or fluticasone 200-400 microg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes ( n= 31) [14.3 5.3% vs. 3.1 2.4% improvement of forced expiratory volume in one second (FEV(1) ), 0.01], while LTC(4) S genotype-stratified response to inhaled beta-agonist salbutamol (200 microg) was not observed (17.5 2.1% vs. 18.7 2.2% improvement of FEV(1) ). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV(1) ) was correlated with LTC(4) S genotype (P < 0.01) and pretreatment airway reversibility to salbutamol (P < 0.01), but not with sex, age, atopic status, urinary leukotriene E(4) excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC(4) S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P < 0.05). We conclude that LTC(4) S genotype is predictive of the clinical response to a cysLT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.

Administration, Inhalation↗
PubMed2002

FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells.

In the kidney, proteins filtered through glomeruli are reabsorbed by endocytosis along the proximal tubules to avoid renal loss of large amounts of proteins. Recently, neonatal Fc receptor (FcRn), which is involved in the transport of IgG across several epithelial and endothelial cells, was reported to be expressed in renal proximal tubular epithelial cells (RPTECs). However, there has been no direct evidence for receptor-mediated endocytosis of IgG in human RPTECs. To explore physiological roles of FcRn in the proximal tubules, we used the human RPTECs to examine IgG transport. FcRn was expressed in RPTECs and physically associated with beta(2)-microglobulin, preserving the capacity of specific pH-dependent IgG binding. Human IgG was bound to the cell surface of RPTECs in a pH-dependent manner. The human IgG transport assay revealed that receptor-mediated transepithelial transport of intact IgG in RPTECs is bidirectional and that it requires the formation of acidified intracellular compartments. With the use of double immunofluorescence, the internalized human IgG was marked in cytoplasm of RPTECs and colocalized with FcRn. These data define the mechanisms of FcRn-associated IgG transport in RPTEC monolayers. It was suggested that the intact pathway for human IgG transepithelial transport may avoid lysosomal degradation of IgG.

Biological Transport↗