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J Wada

Publications and source records attributed to J Wada.

At least 55 records · Page 3Linked to original sources
PubMed1999

L-selectin and its ligands mediate infiltration of mononuclear cells into kidney interstitium after ureteric obstruction.

It was previously reported that the L-selectin ligands detected by a rat L-selectin and human IgG chimeric molecule (rLEC-IgG) are expressed in the distal tubules of the kidney, where no leukocyte traffic is seen under physiological conditions. In the present study, the role of L-selectin ligands in leukocyte infiltration into the kidney interstitium was investigated using a rat ureteric obstruction model. After ligation of the ureter, ligands for L-selectin rapidly disappeared from tubular epithelial cells and were relocated to the interstitium and peritubular capillary walls, where infiltration of monocytes and CD8(+) T cells subsequently occurred. Mononuclear cell infiltration was significantly inhibited by intravenous injection of a neutralizing monoclonal antibody (MAb) against L-selectin, indicating the possible involvement of an L-selectin-mediated pathway. Interestingly, immunohistochemical studies with a MAb against sulphatide showed that the distribution of sulphatide, known to be one of the candidates of L-selectin ligand, was almost indistinguishable from the staining pattern of rLEC-IgG in both normal and ureteric obstructed kidneys, suggesting that sulphatide and/or related molecule(s) relocated to the renal interstitium were recognized by leukocyte L-selectin, leading to interstitial leukocyte infiltration. In line with this notion, intravenous injection of sulphatide markedly inhibited leukocyte infiltration, suggesting that L-selectin-sulphatide interaction may play a pivotal role in interstitial leukocyte infiltration in the kidney following ureteric obstruction.

Animals↗
PubMed1999

Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli.

AIMS/HYPOTHESIS: Advanced glycation end products are believed to contribute to diabetic microvascular complications by inducing glomerular damage but their role has not been fully clarified. In this study, we explain their central role in the induction of inducible nitric oxide synthase and production of nitric oxide (NO) in streptozotocin-induced diabetic rat glomeruli. METHODS: Localization of carboxymethyllysine, which is one of the chemical components of advanced glycation end products, glomerular expression of inducible nitric oxide synthase and urinary excretion and glomerular production of NO2-/NO3- were examined at 0, 26, 51, and 52 weeks after the induction of diabetes. Therapeutic effects of aminoguanidine were also examined. RESULTS: Carboxymethyllysine was detected in the mesangial area in glomeruli and it progressively accumulated during 52 weeks of observation. Immunohistochemistry and hybridization studies in situ showed that the number of inducible nitric oxide synthase-positive cells was notably increased in diabetic rat glomeruli at 52 weeks. Further, this augmented expression paralleled intraglomerular expression of TNF-alpha and NO2-/NO3- in diabetic rat glomeruli. Treatment with aminoguanidine reduced the expression of TNF-alpha, inducible nitric oxide synthase and intraglomerular NO2-/NO3- production. It also ameliorated proteinuria in diabetic rats. CONCLUSION/INTERPRETATION: This study showed that carboxymethyllysine possibly enhances the expression of inducible nitric oxide synthase by stimulating the expression of TNF-alpha in diabetic rat glomeruli. The carboxymethyllysine-cytokine-NO sequence pathway could be one of the major mechanisms in the development of diabetic nephropathy.

Animals↗
PubMed1999

Screening for genes up-regulated in 5/6 nephrectomized mouse kidney.

BACKGROUND: In diabetic and nondiabetic renal diseases, glomerular hyperfiltration is believed to play a central role in the subsequent progression of glomerulosclerosis and interstitial renal scarring. To identify genes involved in the process of hyperfiltration and hypertrophy, a polymerase chain reaction (PCR)-based subtraction method, that is, representational difference analysis of cDNA (cDNA-RDA), was employed. METHODS: Ten-week-old ICR mice were 5/6 nephrectomized and sham operated. After two weeks, mRNAs were isolated from control and remnant kidneys and were subjected to the cDNA-RDA procedure. RESULTS: We identified 10 known and 9 novel genes. Among 19 clones, 12 clones (8 known and 4 novel) showed 1.5- to 6-fold up-regulation by Northern blot analyses. The remaining seven clones were rarely expressed genes and were barely detected by Northern blot analyses, and their up-regulated expression was confirmed by Southern blot analysis using the PCR-amplified representative amplicons. The known genes included kidney androgen-regulated protein, major urinary protein, lysozyme M, metalloproteinase-3 tissue inhibitor, chaperonin 10, cytochrome oxidase I, epsilon-sarcoglycan, ribosomal protein S3a, G-proteingamma10 subunit, and splicing factor 9G8. All of the isolated known genes have not been reported to be up-regulated in the nephrectomized mouse kidney and suggest the possible role of androgen action, mitochondrial functions, matrix metabolism, cell-matrix interactions, and intracellular signaling events in the initiation of the progressive renal injury of the remnant kidney. Furthermore, cDNA-RDA facilitates the discovery of novel genes, including two kidney-specific genes. CONCLUSIONS: The isolated known and novel genes may be involved in the pathobiological process of initial hyperfiltration and hypertrophy of remnant kidney.

Animals↗
PubMed1999

Role of membrane-type matrix metalloproteinase 1 (MT-1-MMP), MMP-2, and its inhibitor in nephrogenesis.

Extracellular matrix (ECM) proteins, their integrin receptors, and matrix metalloproteinases (MMPs), the ECM-degrading enzymes, are believed to be involved in various biological processes, including embryogenesis. In the present study, we investigated the role of membrane type MMP, MT-1-MMP, an activator pro-MMP-2, in metanephric development. Also, its relationship with MMP-2 and its inhibitor, TIMP-2, was studied. Since mRNAs of MT-1-MMP and MMP-2 are respectively expressed in the ureteric bud epithelia and mesenchyme, they are ideally suited for juxtacrine/paracrine interactions during renal development. Northern blot analyses revealed a single approximately 4.5-kb mRNA transcript of MT-1-MMP, and its expression was developmentally regulated. Inclusion of MT-1-MMP antisense oligodeoxynucleotide (ODN) in the culture media induced dysmorphogenetic changes in the embryonic metanephros. MMP-2 antisense ODN also induced similar changes, but they were relatively less; on the other hand TIMP-2 antisense ODN induced a mild increase in the size of explants. Concomitant exposure of MT-1-MMP and MMP-2 antisense ODNs induced profound alterations in the metanephroi. Treatment of TIMP-2 antisense ODN to metanephroi exposed to MT-1-MMP/MMP-2 antisense notably restored the morphology of the explants. Specificity of the MT-1-MMP antisense ODN was reflected in the selective decrease in its mRNA and protein expression. The MT-1-MMP antisense ODN also resulted in a failure in the activation of pro-MMP-2 to MMP-2. These findings suggest that the trimacromolecular complex of MT-1-MMP:MMP-2:TIMP-2 modulates the organogenesis of the metanephros, conceivably by mediating paracrine/juxtacrine epithelial:mesenchymal interactions.

Aging↗
PubMed1999

Increased urinary excretion of macrophage-colony-stimulating factor (M-CSF) in patients with IgA nephropathy: tonsil stimulation enhances urinary M-CSF excretion.

Upper respiratory tract infection including chronic tonsillitis is considered to be involved in the onset and/or the progression of IgA nephropathy. It is well known that deterioration of urinary findings occurs after episodes of upper respiratory tract infection in patients with IgA nephropathy. We previously showed that the expression of macrophage-colony-stimulating factor (M-CSF) is increased in the glomeruli of patients with IgA nephropathy and correlated with glomerular mesangial proliferation, suggesting that M-CSF plays an important role in the progression of IgA nephropathy. In the present study, we measured the serum and urinary concentrations of M-CSF in patients with IgA nephropathy associated with chronic tonsillitis. Furthermore, we evaluated the effects of the local provocation test of tonsils (mechanical tonsil stimulation) on the serum and urinary concentrations of M-CSF in the following three groups: (1) IgA nephropathy with severe mesangial proliferation, (2) IgA nephropathy with mild mesangial proliferation, and (3) patients with chronic tonsillitis without renal disease. The serum and urinary levels of M-CSF in the groups with severe and mild IgA nephropathy were significantly higher than those in the chronic tonsillitis group. The urinary M-CSF level but not the serum M-CSF level was positively correlated with the degrees of mesangial proliferation and glomerular M-CSF expression in the renal biopsy specimens. The urinary M-CSF concentration was significantly increased after tonsillitis stimulation in both mild and severe IgA nephropathy groups. Enhanced urinary excretion of M-CSF prolonged for 7 days after tonsil stimulation in the severe IgA nephropathy group; in contrast, the urinay M-CSF level was increased for only 2 days after tonsil stimulation in the mild IgA nephropathy group. The urinary M-CSF level was not changed in the chronic tonsillitis group after tonsil stimulation. The serum concentrations of M-CSF were not changed after tonsil stimulation in these three groups. Our present results suggest that tonsil stimulation contributes to the progression of IgA nephropathy via enhancement of glomerular production of M-CSF. The urinary excretion of M-CSF may be a useful predictor to evaluate the relevance of chronic tonsillitis to the disease and the indication of tonsillectomy in patients with IgA nephropathy.

Adult↗
PubMed1999

Differential distribution of insulin-like growth factor-1 and insulin-like growth factor binding proteins in experimental diabetic rat kidney.

Insulin-like growth factor-1 (IGF-1) is a peptide growth factor, and its activity is modulated by interaction with the family of IGF binding proteins (IGFBP-1 to 6). IGF-1 is detected in rat kidney and has metabolic and growth effects. To explore the possible involvement of IGFBPs in glomerular hypertrophy in streptozotocin (STZ)-induced diabetic rat, the immunolocalization of IGF-1 and IGFBPs were investigated. IGF-1 was gradually increased in the glomeruli of diabetic rats and correlated with glomerular hypertrophy. IGFBP-1 was transiently increased at 1 week after the STZ injection and declined to control level during the following period. In contrast, IGFBP-4 was increased in the diabetic glomeruli throughout the observation period. With insulin treatment, the levels of IGF-1, IGFBP-1 and 4 were normalized and glomerular hypertrophy was prevented. Initial glomerular hypertrophy of diabetic nephropathy is a related IGF-1 action, which may be modulated by IGFBP-1 and 4.

Animals↗
PubMed1999

Genetic analysis of wild polioviruses towards the eradication of poliomyelitis from the Western Pacific Region.

Since a laboratory network to eradicate poliomyelitis in the Western Pacific Region started in 1991, the Department of Virology II, National Institute of Infectious Diseases, has been functioning as a Regional Reference Laboratory. From 1992 to 1998, we examined 5453 stool samples collected from 3501 patients with acute flaccid paralysis in Cambodia, Vietnam, and Laos, and we isolated 392-type 1 and 10-type 3 wild polioviruses. As a result of the extensive immunization during this time in this area, the numbers of poliomyelitis cases by wild polioviruses have drastically decreased. In 1997, only nine type 1 wild polioviruses were isolated. Eight out of the nine cases were found in Cambodia, and one was in mid-Vietnam. Since then no wild polioviruses have been isolated in the Western Pacific Region for more than two years. A nucleotide sequence analysis of these 1997 isolates indicated that they all belonged to the same strain that has been prevailing in the Indochina area, suggesting the complete interruption of wild poliovirus transmission in the region.

Acute Disease↗
PubMed1998

Characterization of mammalian translocase of inner mitochondrial membrane (Tim44) isolated from diabetic newborn mouse kidney.

Mammalian translocase of mitochondrial inner membrane (mTim44) was isolated during representational difference analysis of cDNA from diabetic mouse kidney. Streptozotocin-induced diabetic mouse kidney cDNA was prepared and subtracted by normal mouse kidney cDNA. By using one of the isolated cDNA fragments as a screening probe, full-length cDNA of mTim44 was isolated from lambdaZAP kidney cDNA library. At the nucleotide level, mTim44 did not exhibit significant homology with any known genes; however, at the amino acid level, it had 50% similarity and 29% identity with yeast Tim44. C-terminal FLAG epitope-tagged mTim44 fusion protein was transiently expressed in COS7 cells. By using anti-FLAG epitope M2 monoclonal antibody, mTim44 was found to have its subcellular localization associated with mitochondria. By immunoelectron microscopy, mTim44 was seen in the paracrystalline structures within the mitochondria, as well as in their cristae. Mitochondrial import assay of in vitro translated mTim44 indicated that its precursor product ( approximately 50 kDa) was imported and proteolytically processed to a mature approximately 44-kDa protein, and its translocation was inner membrane potential (DeltaPsi)-dependent. Imported mTim44 was protected from protease digestion in which outer membranes were selectively permeabilized with digitonin. The mature form of mTim44 could be recovered in the supernatant of sonicated mitochondrial membrane fraction treated with 0.1 M Na2CO3, pH 11.5. The data indicate that mTim44 is a mitochondrial inner membrane protein, one of the members of the mammalian TIM complex and up-regulated in hyperglycemic states.

Amino Acid Sequence↗
PubMed1998

Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy.

The overproduction of nitric oxide (NO) is reported in the diabetic kidney and considered to be involved in glomerular hyperfiltration. The precise mechanism of NO production in the diabetic kidney is, however, not known. In this report, we compare the localization of endothelial cell nitric oxide synthase (ecNOS) isoform expression in the kidney tissue of streptozotocin (STZ)-induced diabetic rats and 5/6 nephrectomized rats and clarify the pivotal role of ecNOS for the glomerular hyperfiltration in the early stages of diabetic nephropathy. In diabetic rats, the diameters of afferent arterioles, the glomerular volume, creatinine clearance, and urinary NO2/NO3 were increased after the induction of diabetes. Efferent arterioles were, however, not altered. Insulin or L-NAME treatment returned the diameters of afferent arterioles, glomerular volume, creatinine clearance, and urinary NO2/NO3 to normal. The expression of ecNOS in afferent arterioles and glomeruli of diabetic rats increased during the early stages of the disease, but was not altered in efferent arterioles. Treatment with either insulin or L-NAME decreased ecNOS expression in afferent arterioles and in glomeruli. In contrast, the ecNOS expression was upregulated in both afferent and efferent arterioles and in the glomeruli of 5/6 nephrectomized rats, where the dilatation of afferent and efferent arterioles and glomerular enlargement were observed. Treatment with L-NAME ameliorated the ecNOS expression and dilatation of arterioles. We conclude that enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells in response to the hyperglycaemic state could cause preferential dilatation of afferent arterioles, which ultimately induces glomerular enlargement and glomerular hyperfiltration.

Animals↗
PubMed1998

Heterogeneous carbamoylphosphate synthetase I expression in testicular transplants of fetal mouse liver.

Expression of carbamoylphosphate synthetase I (CPSI; EC 6.3.4.16) was examined immunohistochemically in normal development of the mouse liver, and in testicular transplants of fetal liver fragments. CPSI started to be expressed in all hepatocytes around 15 days of gestation, and became heterogeneous (i.e. absent from pericentral hepatocytes) around 2 weeks after birth. Most hepatocytes in fetal liver fragments placed for 2 months under the testicular capsule expressed this enzyme except for the pericentral ones, most of which were positively stained with anti-glutamine synthetase (GS; EC 6.3.1.2) antiserum. This distribution resembled that in the adult liver. The steep change in CPSI immunostaining in liver lobules suggests that the microenvironment tightly connected to the central veins plays an important role in the suppression of CPSI expression in the pericentral hepatocytes. Some pericentral hepatocytes were also negative for both enzymes. Thus, control mechanisms of CPSI expression may be different from those of GS expression in pericentral hepatocytes.

Animals↗
PubMed1998

Therapeutic effects of prostacyclin analog on crescentic glomerulonephritis of rat.

Prostacyclin (PGI2) is known to have a relaxative action on vascular smooth muscle, an inhibitory action against platelet activation and neutrophil function. Previous studies showed the preventive effects of PGI2 on lupus nephritis and Thy-1 nephritis, although the mechanism has not been clarified. Glomerular endothelial expression of intercellular adhesion molecule-1 (ICAM-1) is up-regulated in experimental and human glomerular diseases, and is known to facilitate leukocyte infiltration into the glomeruli, which ultimately induces the various glomerular injuries. In the present study, we evaluated the therapeutic effects of PGI2 on a rat model for crescentic glomerulonephritis and investigated its putative mechanism in relation to ICAM-1-mediated leukocyte recruitment. Wistar-Kyoto (WKY) rats were injected with nephrotoxic serum and received continuous intraperitoneal infusion of PGI2. PGI2 dramatically decreased proteinuria (123.0 +/- 18.8 vs. 31.6 +/- 4.5), crescent formation and deposition of fibrinogen in the glomeruli, while the deposition of rabbit IgG, rat IgG and rat C3 along the capillary walls was not changed. Furthermore, intraglomerular expression of ICAM-1 and infiltration of macrophages were significantly suppressed by administration with PGI2. In contrast, influx of CD4 or CD8 positive cells was not altered. The present results suggest that PGI2 shows the preventive effects on experimental crescentic glomerulonephritis by inhibiting intraglomerular coagulation and ICAM-1-mediated macrophage-glomerular endothelial cell adhesive pathway.

Animals↗
PubMed1998

Cytokine interactions promote synergistic fibronectin accumulation by mesangial cells.

BACKGROUND: The development of glomerulosclerosis has been associated with the presence of the cytokines transforming growth factor-beta 1 (TGF-beta 1), tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-1 beta (IL-1 beta), at some stage in the glomerulus. To better understand the role of these cytokines in the scarring process their effect on rat mesangial cell fibronectin production was investigated. METHODS: Mesangial cells were exposed to 10 ng/ml of either TGF-beta 1, TNF-alpha, or IL-1 beta or to TGF-beta 1 in combination with TNF-alpha or IL-1 beta. Tissue culture supernatants and cell lysates were assayed for fibronectin. Supernatants were also assayed for TGF-beta 1. Northern blot analyses probing for fibronectin, transin, TIMP-1 and TGF-beta 1 were carried out on RNA extracted from mesangial cells exposed to individual and combinations of cytokines. RESULTS: Individually these cytokines were only able to induce modest increases in fibronectin protein levels. However, when mesangial cells were exposed to TGF-beta 1 in combination with either TNF-alpha or IL-1 beta then fibronectin levels were synergistically up-regulated approximately fivefold over unstimulated levels. Northern analysis demonstrated that fibronectin mRNA levels in the combination were also synergistically increased. In contrast, rat transin gene expression in the combinations was reduced to well below levels induced by TNF-alpha and IL-1 beta individually. In addition, synergistic up-regulation of both TGF-beta 1 protein and message by the cytokine combinations was also observed. TGF-beta 1: TNF-alpha and TGF-beta 1: IL-1 beta induced additive increases in TIMP-1 (tissue inhibitor of metalloproteinases-1) mRNA levels. CONCLUSIONS: These data illustrate that complex interactions can occur between cytokines within the glomerulus modulating both matrix synthetic and degradation pathways. These could initiate the scarring process and the development of glomerulosclerosis.

Animals↗
PubMed1998

Ultrastructure of mesangial type III collagen deposition in a patient with IgA nephropathy.

We report a case of IgA nephropathy with focal and segmental deposition of type III collagen in mesangium, confirmed by immunohistochemical and electron microscopic methods. Tissue negative staining showed that focal and segmental fibrotic lesions in the mesangial area consisted of disarrayed or curled striated collagen fibers and striated membranous structures. Diabetes mellitus, hypertension, and advanced glomerular sclerosis were absent in this case, and mesangial cells surrounding the type III collagen showed vacuolar degeneration revealed by electron microscopy. Production of type III collagen may be the marker for phenotypic change of mesangial cells in immune-mediated glomerular diseases.

Biopsy↗
PubMed1998

Relevance of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis.

Mammalian nephrogenesis begins by the reciprocal interaction of the ureteric bud with the undifferentiated mesenchyme. The mesenchyme differentiates into an epithelial phenotype with the development of the glomerulus and proximal and distal tubules. At the same time, the mesenchyme stimulates the branching morphogenesis of the ureteric bud that differentiates into the collecting ducts. These inductive interactions and differentiation events are modulated by a number of macromolecules, including the extracellular matrix (ECM), integrin receptors, and cell adhesion molecules. Many of these macromolecules exhibit spatiotemporal developmental regulation in the metanephros. Some are expressed in the mesenchyme, whereas others appear in the ureteric bud epithelia. The molecules expressed in the mesenchyme or at the epithelial:mesenchymal interface may serve as ligands while those in the epithelia serve as the receptors. In such a scenario the ligand and the receptor would be ideally suited for epithelial:mesenchymal paracrine/juxtacrine interactions that are also influenced by RGD sequences and Ca2+ binding domains of the ECM proteins and their receptors. This review addresses the role of such interactions in metanephric development.

Animals↗
PubMed1998

Isolation of rat fibrillin-1 cDNA and its relevance in metanephric development.

The role of fibrillin-1 in metanephrogenesis was investigated. Fibrillin-1 cDNA was isolated from the rat kidney cDNA library and sequenced, and its spatiotemporal expression was studied. It had approximately 88% homology with human fibrillin-1 and had Ca2+ binding epidermal growth factor-like domains, transforming growth factor-beta binding protein motifs, and an RGD binding site. Northern blot analysis revealed an approximately 10-kb transcript, and fibrillin-1 expression was developmentally regulated. In situ hybridization and immunofluorescence studies indicated that at day 15 of gestation, fibrillin-1 is expressed in the metanephric mesenchyme. At day 18, its expression was confined to nascent blood vessels and glomeruli, and it increased in the newborn and neonatal kidneys. Immunoprecipitation revealed an approximately 300-kDa band by SDS-PAGE. Treatment with fibrillin-1 antisense oligodeoxynucleotide induced marked dysmorphogenesis of the embryonic metanephroi. Concomitantly, the fibrillin-1 mRNA, antibody reactivity in the metanephroi, and fibrillin-1-specific radioincorporation were reduced. These data indicate that, like alphavbeta3 integrin, a known morphogen and a putative receptor of fibrillin-1, the fibrillin-1 modulates events related to early organogenesis and possibly also the vascularization of the rat kidney.

Amino Acid Sequence↗
PubMed1998

Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy.

Mannan binding protein (MBP) is a C-type lectin and has a high affinity to mannose and N-acetyl glucosamine. It is also known to activate C4 and C2 without C1 component, which is called 'lectin pathway'. We now report the presence of MBP and MBP-mediated complement activation in renal glomeruli of IgA nephropathy patients using an immunohistochemical method. In 7 of 42 cases with IgA nephropathy, MBP was detected in the glomerular mesangial area and colocalized with IgA1. In 19 cases with other types of IC-mediated glomerulonephritis including lupus nephritis and membranous nephropathy or without nephritis, MBP was not detected in the glomerulus. The C2- and/or C4-positive rate was 87.5% in the MBP-positive group and 20% in the MBP-negative group of IgA nephropathy. In addition, MBP-positive cases showed marked mesangial cell proliferation, lower creatinine clearance (53.4 +/- 10.0 vs. 77. 8 +/- 4.7 ml/min) and higher urinary protein excretion (2.5 +/- 0.9 vs. 0.9 +/- 0.2 g/day) compared with MBP-negative cases. These findings suggested that MBP was involved in glomerular complement activation through the lectin pathway and thus induced glomerular injury of IgA nephropathy. Since oligosaccharide chain alterations such as reduced sialic acid and galactose of IgA1 molecule have been reported in IgA nephropathy patients, MBP might bind to the IgA1 molecule via interaction between MBP and sugar chain.

Adult↗