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Biomedical subjects

A Tojo

Publications and source records attributed to A Tojo.

At least 73 records · Page 4Linked to original sources
PubMed1997

Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase.

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.

Animals↗
PubMed1997

Differential localization of s and e antigens in hepatitis B virus-associated glomerulonephritis.

We report here a case of membranous glomerulonephritis associated with chronic hepatitis B (HB) virus infection and describe differential localization of HB antigens in glomeruli. The patient showed mild proteinuria and was positive for hepatitis B surface (HBs) antigen, hepatitis B envelope (HBe) antigen, and antibody to hepatitis B core (HBc) antigen in the serum. The antibody against hepatitis C was negative. A renal biopsy revealed membranous glomerulonephritis with mesangial proliferation. The immunohistochemical studies using monoclonal antibodies localized the HBe antigen along the capillary wall and the HBs antigen in the mesangial area. The immunoelectron microscopic study confirmed the localization of HB antigens: HBe antigen was located in the subepithelial and intramembranous electron dense deposits and HBs antigen in the mesangial deposits. Our present results provide the first report of the differential localization of HB antigens in glomeruli at both the light and electron microscopic levels. The differential localization of HB antigens will provide insight into the pathogenesis of membranous glomerulonephritis.

Adult↗
PubMed1997

Location and action of angiotensin II type 1 receptor in the renal microcirculation.

To localize angiotensin II type 1a (AT-1a) receptor and to reveal the physiological roles of angiotensin II in the renal microcirculation, we investigated the AT-1a gene deficient mice, generated by a targeted replacement of the AT-1a receptor loci by the lacZ gene (Sugaya et al, J Biol Chem 270: 18719, 1995). Immunohistochemical localization of beta-galactosidase was performed in the heterozygous mutant mice to reveal the expression sites of AT-1a. The AT-1a receptor (that is, beta-galactosidase) was expressed both in the afferent and efferent arteriolar smooth muscles and also in the mesangial cells. The effect of angiotensin II on glomerular arterioles was directly observed using the hydronephrotic mice. Angiotensin II similarly constricted both the afferent and efferent arterioles in the wild-type and heterozygous mutant mice in a dose-dependent manner. This constriction was completely abolished by an AT-1 antagonist, CV-11974. In the homozygous null mutant mice, however, angiotensin II did not affect the arterioles at all. Electron microscopic studies revealed that the mesangial cells made contact with the glomerular basement membrane (GBM) at the capillary neck and also with each other in the wild-type mice. However, in the homozygous null mutant mice, the mesangial cells lost the contact either with GBM or with each other and thus the capillary neck became remarkably wider. The mesangial matrix area appeared loose and enlarged, suggesting impaired mesangial matrix formation. In conclusion, via the AT-1a receptor, angiotensin II equally constricts both the afferent and efferent arterioles and plays an essential role in maintaining the normal glomerular function and structure.

Angiotensin II↗
PubMed1996

A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3.

Interleukin 3 (IL-3) not only induces DNA synthesis of haematopoietic cells but also maintains their viability by suppressing apoptosis. IL-3 stimulates tyrosine phosphorylation of the Shc adaptor protein and thereby formation of a complex of Shc with Grb2 at phosphorylated tyrosine (Y) residue 317-Shc. This pathway is implicated in Ras/mitogen-activated protein kinase (MAPK) activation towards c-fos gene expression. We examined the possible involvement of Shc in the antiapoptotic activity of IL-3. Conditional overexpression of the Shc SH2 domain, a dominant-negative mutant of Shc, was found to induce apoptosis of IL-3-dependent Ba/F3 cells along with a reduction of c-myc gene expression. Apoptosis was rescued by the exogenously introduced c-myc gene. Since we identify novel tyrosine phosphorylation sites of Shc: Y239 and Y240, their role on cell survival was tested by mutational analysis. Ba/F3 cells expressing mutant Shc Y317F, which is unable to stimulate efficiently the Ras pathway, still showed resistance to apoptosis. However, cells expressing Shc Y239/240F, which is able to stimulate the Ras pathway, were sensitive to apoptosis. In these cells, induction of the c-myc gene was reduced. These findings suggest that a new signalling pathway for cell survival is generated from Y239/240 of Shc to the nuclei involving c-myc gene expression.

Apoptosis↗
PubMed1996

Nonmuscle and smooth muscle myosin heavy chain expression in rejected cardiac allografts. A study in rat and monkey models.

BACKGROUND: Diagnosis of acute rejection and graft arteriosclerosis (chronic rejection) is critical to the success of cardiac transplantation, but accurate diagnosis is often difficult. We have reported that there are three types of vascular myosin heavy chain (MHC) isoforms: SM1, SM2, and SMemb. SM2 is specifically expressed in differentiated smooth muscle cells (SMCs). SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of fetal aorta. METHODS AND RESULTS: To evaluate the usefulness of MHC expression for diagnosis and analysis of acute and chronic rejection, heterotopic cardiac transplantation was performed in rats and monkeys. Immunohistochemistry, electron microscopy, and Northern blot assay were performed to evaluate MHC expression. SMemb was expressed in spindle-shaped cells located in acutely rejected myocardium in the rats and monkeys. These cells were also observed in areas lacking cellular infiltration. These SMemb-positive cells were activated fibroblasts or myofibroblasts. SMemb mRNA was enhanced parallel to the progression of acute rejection. In the coronary arteries of chronically rejected allografts, enhanced SMemb and reduced SM2 expression was observed in both thickened intima and media. The reduced medial SM2 expression was observed before the intimal thickening occurred. These cells were phenotypically modulated SMCs. CONCLUSIONS: Altered expression of MHC isoforms is a sensitive indicator in the diagnosis of acute and chronic cardiac rejection. The pathophysiology of this alteration in MHC isoform expression should be studied further to elucidate the pathogenesis of cardiac rejection.

Animals↗
PubMed1996

Differentiation effect of acyclic retinoid on acute promyelocytic leukemia cells.

Acyclic retinoid (all-trans-3, 7, 11, 15-tetramethyl-2, 4, 6, 10, 14-hexadecapentaenoic acid) binds cellular retinoic acid-binding protein with an affinity similar to that of all-trans retinoic acid and induces differentiation of human hepatoma cell lines and a human acute myelogenous leukemia cell line (HL-60). We investigated the in vitro efficacy of acyclic retinoid to induce the differentiation of acute promyelocytic leukemia (APL) cells using primary cultured cells obtained from 11 APL patients. Five days' incubation with acyclic retinoid effected a dose-dependent induction of differentiation. Cells from eight patients showed maximum differentiation at 10(-6) M acyclic retinoid. Cells from one patient required 10(-5) M for maximum differentiation, while those from two patients exhibited moderate differentiation at 10(-5) M. Five days' incubation with acyclic retinoid (10(-7) approximately 10(-5) M) did not affect the viability or number of cells from any patient except one, whose cells showed a slight decrease in viability at 10(-5) M. Thus, we conclude that acyclic retinoid induced the differentiation of primary cultured APL cells at concentrations of 10(-6) approximately 10(-5) M, a range at which it is not toxic.

Antineoplastic Agents↗
PubMed1996

Expression of a nonmuscle myosin heavy chain in glomerular cells differentiates various types of glomerular disease in rats.

To characterize the phenotypic modulation of mesangial and glomerular epithelial cells, we investigated the expression of a nonmuscle type myosin heavy chain, SMemb, and alpha-smooth muscle actin (alpha-SM actin) in rat experimental glomerular diseases, which included anti-Thy 1 nephritis, 5/6 nephrectomy, diabetes, and anti-glomerular basement membrane nephritis. SMemb was only slightly expressed in normal glomerular epithelial cells but not in mesangial cells. In the anti-Thy 1 nephritis rats, both SMemb and alpha-SM actin were most conspicuously induced in mesangial cells. However, the expression profile was shifted from alpha-SM actin to SMemb dominant pattern over the course of glomerulonephritis. The expression of SMemb was also increased in epithelial cells in this model. In the other three models, glomerular cells did not express alpha-SM actin, but did so for SMemb. In the nephrectomized and the diabetic rats SMemb was newly expressed in mesangial cells at earlier stages, but at later stages was remarkably enhanced in epithelial cells when severe glomerular hypertrophy developed. In the anti-GBM nephritis rats, SMemb expression was increased in epithelial cells. In all models examined, mesangial and epithelial expression of SMemb was confirmed by immunoelectron microscopy, and enhanced expression of SMemb mRNA in glomeruli was verified by RNase protection assay. We conclude from these results that glomerular cells change their phenotypes differently depending on various types of glomerular diseases. These phenotypic changes in glomerular cells can be revealed by the combined immunostaining for SMemb and alpha-SM actin. SMemb is especially useful to detect both mesangial and glomerular epithelial cell activation in these glomerular disease models. Understanding the functional difference and regulatory mechanisms of these cytoskeletal proteins will provide insight into the pathogenesis and progression of glomerular diseases.

Actins↗
PubMed1996

Endothelin-mediated effect of erythropoietin on blood pressure and renal hemodynamics in hypertensive rats.

Erythropoietin (EPO) has been reported to induce hypertension in hemodialysis patients with family history of hypertension. In this study, to reveal the mechanism of EPO-induced hypertension, we examined the acute effect of EPO on blood pressure (BP) and renal hemodynamics in genetically hypertensive rats, and we also tested the effect of BQ-123, an endothelin ETA-receptor blocker, on EPO-induced changes in hemodynamics. Male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), aged 9-12 wk, were anesthetized, and BP was monitored through the carotid artery. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after an intravenous injection of EPO (1,000 U/kg body wt). In another group of SHR, BQ-123 was continuously infused (1.2 mg.kg body wt-1.h-1) during the experiments. The acute injections of EPO increased BP significantly in SHR in a dose-dependent manner, whereas WKY did not show a significant increase in BP after EPO injections. The effect of EPO on BP in SHR was blocked by BQ-123. In SHR, an acute injection of EPO decreased RPF significantly (from 1.78 +/- 0.16 to 1.49 +/- 0.18 ml.min-1.100 g body wt-1, P < 0.05) without a change in GFR, whereas WKY did not show significant changes in either RPF or GFR. The effect of EPO on RPF in SHR was completely blocked by BQ-123 (from 1.92 +/- 0.26 to 1.88 +/- 0.28 ml.min-1.100 g wt-1, NS). EPO caused a significant increase in plasma endothelin ET-1 in SHR (from 2.3 +/- 0.6 to 6.3 +/- 1.6 pg/ml, P < 0.05), but not in WKY. In conclusion, acute administration of EPO raised blood pressure and reduced RPF in SHR, and these vasoconstrictive effects of EPO are mediated via ETA receptors by an enhanced ET-1 release.

Animals↗
PubMed1996

Nitric oxide release from kidneys of hypertensive rats treated with imidapril.

To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescense assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10(-8) mol/L) of both renal perfusion pressure (stroke-prone SHE 42 +/- 4% versus Wistar-Kyoto rats [WKY] 58 +/- 4% [mean +/- SE], P < .01) and nitric oxide release (stroke-prone SHR +7.6 +/- 2.1 versus WKY +29.7 +/- 9.7 fmol/min per gram of kidney wt, P < .01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56 +/- 3%; nitric oxide release, +27.1 +/- 6.4 fmol/min per gram of kidney wt; both P < .01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA-salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA-salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Effect of trichlormethiazide and captopril on nitric oxide synthase activity in the kidney of deoxycorticosterone acetate-salt hypertensive rats.

Nitric oxide (NO) production is reduced in patients with essential hypertension and in some experimental models. We have investigated the effect of trichlormethiazide and captopril on NO synthase (NOS) activity and glomerular damage in the kidney of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. DOCA-salt rats were induced with weekly injections of DOCA (30 mg/kg body weight (BW) and 1% saline in drinking water after right nephrectomy. As antihypertensive therapies, CAP (captopril, 40 mg/kg BW) and TCM (trichlormethiazide, 10 mg/kg BW) were given after induction of DOCA-salt hypertension. The increased blood pressure was significantly lowered by TCM, but not by CAP after 5 weeks. Nitrite production in kidney slices was suppressed in DOCA-salt rats, and immunoreactivity for both brain-type NOS (B-NOS) in macula densa and endothelial-type NOS (EC-NOS) in renal vessels was decreased. TCM significantly increased the nitrite production in the kidney slices and B-NOS immunoreactivity, whereas these changes were less in CAP. Glomerulosclerosis score was significantly higher in DOCA-salt rats, and TCM ameliorated renal damage more effectively than CAP. These results indicate that the reduced nitrite production in the kidney of DOCA-salt hypertensive rats was increased more effectively by trichlormethiazide than by captopril, via increased immunoreactivity for B-NOS in the macula densa, and prevented renal damage.

Animals↗
PubMed1996

Cutaneous chronic graft-versus-host disease localized to the field of total lymphoid irradiation.

A 20-year-old woman with aplastic anemia underwent bone marrow transplantation from an HLA-identical sibling after total lymphoid irradiation (TLI) and cyclophosphamide (CY). The post-transplant course was uneventful. CYA was discontinued on day 221. Three weeks later, the patient developed cutaneous GVHD precisely localized to the field of TLI. No other organs were involved. Immunohistochemical staining of the affected skin was strongly positive for ICAM-1, PECAM-1 and ELAM-1; normal skin was only weakly positive for ICAM-1. CYA was restarted, and the skin lesions disappeared. TLI may contribute to an unusual presentation of cutaneous GVHD associated with specific expression of adhesion molecules.

Adult↗
PubMed1996

Effects of antihypertensive drugs on nitric oxide synthase activity in rat kidney.

Nitric oxide production has been reported to be reduced in hypertensive patients. In this study, we investigated the effects of antihypertensive drugs such as calcium channel blocker, amlodipine, alpha 1-adrenoceptor blocker, doxazosin and angiotensin converting enzyme (ACE) inhibitor, imidapril on nitric oxide synthase (NOS) activity in the kidneys of L-NAME-induced hypertensive rats. An increased blood pressure in L-NAME-induced hypertensive rats was significantly decreased by these antihypertensives to the same extent at four weeks. Nitrite production from the kidney slices was significantly suppressed in L-NAME-induced hypertensive rats. This suppression of nitrite production was reversed to the control level in the rats treated with amlodipine, and significantly enhanced by doxazosin and imidapril. Immunoreactivity for both the brain-type NOS in the macula densa and endothelial cell-type NOS in renal vasculature was diminished in L-NAME rats, and antihypertensive therapies, especially doxazosin and imidapril, increased NOS immunostaining. The increased glomerulosclerosis score in the L-NAME group was significantly lowered by the treatment with doxazosin and imidapril. In conclusion, a decreased NOS activity in L-NAME-induced hypertensive rats was significantly increased by alpha 1-adrenoceptor blockers and ACE inhibitors in the kidney, and this increased NOS activity may have a role in the prevention of glomerulosclerosis.

Adrenergic alpha-Antagonists↗
PubMed1996

Hypertensive glomerular damage as revealed by the expression of alpha-smooth muscle actin and non-muscle myosin.

The aim of this study was to determine the phenotypic modulation in mesangial cells of glomeruli damaged by hypertension. Salt-loaded stroke-prone spontaneously hypertensive rats were untreated or treated with a calcium antagonist, manidipine (2 mg/kg/day) for eight weeks. In normotensive Wistar-Kyoto rats, alpha-smooth muscle actin was not expressed in any glomerular cells and a non-muscle myosin heavy chain isoform, SMemb, was slightly expressed in glomerular visceral epithelial cells. In the untreated hypertensive rats, the glomeruli showed sclerosis to various degrees and expressed alpha-smooth muscle actin and SMemb. Normal expression of SMemb in the epithelial cells disappeared. Notably, alpha-smooth muscle actin-positive fibroblast-like cells appeared in the interstitium, especially around the Bowman's capsules. Manidipine ameliorated the glomerulosclerosis and reduced the expression of alpha-smooth muscle actin in mesangial cells. In conclusion, the mesangial cells changed their phenotypes and expressed alpha-smooth muscle actin and SMemb in the glomeruli during the development of hypertensive renal damage. These phenotypically changed mesangial cells are considered to be activated and to produce various kinds of cytokines and extracellular matrix, which leads to glomerulosclerosis. Manidipine attenuated the glomerular damage and the phenotypic changes. The functional relevance of phenotypic changes in these cells should be elucidated in future studies.

Actins↗
PubMed1996

[Bronchiolitis obliterans organizing pneumonia (BOOP) after allogeneic bone marrow transplantation].

We report a patient who underwent allogeneic bone marrow transplantation for ALL. The patient presented low grade fever, cough and dyspnea at day 3 after after bone marrow transplantation. Imaging studies showed bilateral patchy infiltrates on chest X-ray and chest CT. Though treated by antibiotics, chest auscultation recognized marked bilateral inspiratory crackles. Transbronchial lung biopsy performed on day 34 showed bronchiolitis obliterans and an organizing interstitial pneumonia. The patient was treated with methylprednisolone and follow up computed tomography findings improved.

Administration, Oral↗
PubMed1995

Down-modulation of c-kit mRNA and protein expression by erythroid differentiation factor/activin A.

We examined the effects of erythroid differentiation factor (EDF)/activin A on the expression of c-kit mRNA and protein in murine erythroleukemia (MEL) cells. EDF/activin A induced MEL cells to benzidine positive cells. Northern blot analysis showed that the c-kit mRNA expression was reduced synchronously with increase of beta-globin and uroporphyrinogen decarboxylase gene expression during EDF/activin A induced erythroid differentiation. Scatchard analysis indicated that the cell surface receptor number was reduced without change of affinity during differentiation. Our results suggest that EDF/activin A may act as a natural regulator of erythropoiesis with modulation of c-kit gene expression.

Activins↗
PubMed1995

Expression of immunoreactive nitric oxide synthase isoforms in rat kidney. Effects of dietary salt and losartan.

Immunohistochemical studies have shown expression of two different isoforms of NOS in the juxtaglomerular apparatus (JGA). Antibodies to a Ca(++)-calmodulin dependent isoform purified from rat brain (B-NOS) label the macula densa cells whereas antibodies to an isoform purified from rat aortic smooth muscle cells in culture (VSM-NOS) induced with lipopolysaccharide and interferon gamma label the afferent arteriole. Since dietary salt intake and angiotensin II (Ang II) are determinants of renal NO generation, we have tested the hypothesis that salt intake can regulate the immunohistochemical expression of these NOS isoforms through an effect of Ang II. In 4 of 5 paired studies, the immunostaining for both B-NOS and VSM-NOS was more intense in rats that had received a low salt (LS), compared to a high salt (HS), diet. Infusion of the Ang II type 1 (AT1) receptor antagonist, losartan, enhanced the intensity of immunoreactive staining for both isoforms. In conclusion, the immunohistochemical expression of NOS isoforms in the JGA is increased by dietary salt restriction; this effect cannot be ascribed to Ang II acting on type 1 receptors.

Amino Acid Oxidoreductases↗
PubMed1995

[Targeted toxin therapy in the treatment of leukemia].

A chimeric toxin in which the cell surface binding domain of Pseudomonas exotoxin was replaced with mature human granulocyte colony-stimulating factor (G-CSF) was produced in Escherichia coli, partially purified and tested for its biological activity on a G-CSF-dependent murine myeloid leukemia cell line, NFS60. This fusion protein, termed as G-CSF-PE40, can displace [125I] G-CSF binding to its receptor. After 48 hrs incubation in the presence of G-CSF, G-CSF-PE40 inhibited protein synthesis and revealed cytotoxicity in NFS60 cells in a concentration dependent manner. The half maximal dose of G-CSF-PE40 for protein synthesis inhibition (ID50) in NFS60 cells was estimated at around 100pM. Additionally, relatively low concentration of G-CSF-PE40 stimulated DNA synthesis in NFS60 cells after 16 hrs' incubation in the absence of G-CSF, suggesting that G-CSF-PE40 also can transduce a transient mitogenic signal. Thus, G-CSF-PE40 may be useful in the selective elimination of myeloid cells expressing G-CSF receptors, especially in combination with chemotherapeutic agents like cytosine arabinoside.

ADP Ribose Transferases↗