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Biomedical subjects

Michio Nagata

Publications and source records attributed to Michio Nagata.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed to be a monoclonal proliferation of PKD-deficient (PKD(-/-)) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1(-/-) ES cells and Pkd1(+/+) morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both Pkd1(-/-) and Pkd1(+/+) renal tubular epithelial cells in the early stages of cystogenesis. Pkd1(-/-) cyst epithelial cells changed in shape from cuboidal to flat and replaced Pkd1(+/+) cyst epithelial cells lost by JNK-mediated apoptosis in intermediate stages. In late-stage cysts, Pkd1(-/-) cells continued immortalized proliferation with downregulation of p53. These results provide a novel understanding of the cystogenesis of ADPKD patients. Furthermore, immortalized proliferation without induction of p53 was frequently observed in 3T3-type culture of mouse embryonic fibroblasts from Pkd1(-/-) mice. Thus, Pkd1 plays a role in preventing immortalized proliferation of renal tubular epithelial cells through the induction of p53 and activation of JNK.

Animals↗
PubMed2005

Renal graft loss with plasma cell-rich acute rejection in cadaveric renal transplantation: a case report.

We reported a case of renal graft loss in cadaveric renal transplantation. An episode biopsy with renal dysfunction showed plasma cell predominant inflammatory infiltration in the interstitium without a finding of vascular or glomerular rejection, and was diagnosed as plasma cell-rich acute rejection (PCAR). Despite intensive immunosuppressive therapy, the renal histology of repeated biopsies showed persistent plasma cell infiltration and the graft was finally lost. Immunohistological staining and immunoglobulin gene rearrangement studies to estimate the clonality of inflammatory cells revealed that the infiltrating plasma cells were polyclonal in origin. Epstein-Barr virus was not detected by in situ hybridization. From these results, we excluded the possibility of post-transplant lymphoproliferative disorder (PTLD); however, a precise definition and differential diagnosis between PCAR and PTLD has not yet been fully determined. As therapeutic regimens for PCAR and PTLD are different, definite guidelines for diagnosis and treatments of PCAR need to be established.

Acute Disease↗
PubMed2005

Retroperitoneal extragonadal germ cell tumor in a patient with Klinefelter's syndrome.

A 22-year-old man was diagnosed with retroperitoneal seminoma associated with Klinefelter's syndrome. The tumor was 14 x 12 cm in size and surrounded the superior mesenteric artery. He received induction chemotherapy with bleomycin, etoposide and cisplatin (BEP) followed by salvage chemotherapy with paclitaxel, ifosfamide and cisplatin (TIP). The tumor considerably decreased in size and remains as a poorly defined plaque. At the time of writing, he is being followed closely and is free from progression.

Adult↗
PubMed2005

Primary cerebral angiitis containing marked xanthoma cells with massive intraparenchymal involvement--case report--.

A 27-year-old woman was referred to our hospital with mild disorientation, bilateral abducens nerve palsy, and mild left hemiparesis. Magnetic resonance (MR) imaging revealed diffuse mass lesions resembling malignant glioma in the right frontal intraparenchymal region, with enhancement of multiple meningeal and intraparenchymal nodules. Partial resection of the frontal lesion was performed. Histological examination revealed that the specimens consisted of brain tissue, with marked perivascular infiltration of histiocytes and sheets of xanthomatous cells. The diagnosis was primary cerebral angiitis containing marked xanthoma cells. Steroid therapy was administered over 1 week. MR imaging showed that the remaining lesions resolved gradually, and had disappeared 2 years after surgery. No neurological symptoms or recurrence of the tumor has been observed during the 6-year period since the operation.

Abducens Nerve Diseases↗
PubMed2004

Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related Cerebello-oculo-renal syndromes.

Clinicopathological features of the renal disease in Arima syndrome were studied in five autopsy cases. All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure. Decreased urinary concentrating ability and excessive sodium loss were the characteristic laboratory findings. Gross examination showed that both kidneys were small and showed multiple cysts of various sizes. The histological examinations revealed chronic sclerosing tubulo-interstitial nephropathy with cystic tubuli predominantly located at cortico-medullary areas. These observations suggest that the renal disease in Arima syndrome is in accordance with nephronophthisis both clinically and pathologically. Contrary to the previous literature which described that Arima syndrome can be distinguished from other Joubert-related cerebello-oculo-renal syndromes by its unique renal disease, i.e., cystic dysplastic kidney (CDK), our study indicates that the phenotype of the renal disease is common among these syndromes as well as abnormalities in other organs, suggesting the underlying similar molecular mechanisms.

Adolescent↗
PubMed2004

In situ expression of connective tissue growth factor in human crescentic glomerulonephritis.

Connective tissue growth factor (CTGF) has recently been recognized as an important profibrotic factor and is up-regulated in various renal diseases with fibrosis. The present study describes the sequential localization of CTGF mRNA and its association with transforming growth factor (TGF)-beta1 in human crescentic glomerulonephritis (CRGN). Furthermore, we examined the phenotype of CTGF-expressing cells using serial section analysis. Kidney biopsy specimens from 18 CRGN patients were examined using in situ hybridization and immunohistochemistry. CTGF mRNA was expressed in the podocytes and parietal epithelial cells (PECs) in unaffected glomeruli. In addition, it was strongly expressed in the cellular and fibrocellular crescents, particularly in pseudotubule structures. Serial sections revealed that the majority of CTGF mRNA-positive cells in the crescents co-expressed the epithelial marker cytokeratin, but not a marker for macrophages. Moreover, TGF-beta1, its receptor TGF-beta receptor-I, and extracellular matrix molecules (collagen type I and fibronectin) were co-localized with CTGF mRNA-positive crescents. Our results suggest that CTGF is involved in extracellular matrix production in PECs and that it is one of the mediators promoting the scarring process in glomerular crescents.

Activin Receptors, Type I↗
PubMed2004

Treatment with the purine synthesis inhibitor mizoribine for ANCA-associated renal vasculitis.

BACKGROUND: The common treatment for antineutrophil cytoplasmic autoantibody (ANCA)-associated renal vasculitis is oral cyclophosphamide (CYC)-corticosteroid combination therapy. However, there are serious complications associated with long-term use of CYC. In this study, we investigate the efficacy of a purine synthesis inhibitor, mizoribine, for patients at high risk for relapse. METHODS: Our study included 5 patients, 4 patients with myeloperoxidase (MPO)-ANCA-associated renal vasculitis and 1 patient with proteinase 3 (PR3)-ANCA-associated renal vasculitis, who had achieved remission through treatment with methylprednisolone pulse therapy, corticosteroids, and CYC. When their ANCA titers were found to be greater than normal range after remission status, mizoribine treatment was initiated. RESULTS: Median time from initial treatment to first administration of mizoribine was 40.0 months (range, 24 to 51 months). Median follow-up was 13.0 months (range, 6 to 16 months). Before initiation of mizoribine treatment, no patient had experienced relapse and ANCA titers were less than the detectable range in all patients at 3 months before mizoribine administration. When mizoribine administration was started, ANCA titers were elevated in all patients (median MPO-ANCA, 101 ELISA units [EU]; range, 65 to 154 EU; PR3-ANCA, 55 EU), but no new symptoms or signs of relapse were noted. After 2 months of mizoribine treatment, only 1 patient had experienced a relapse; however, ANCA titers had decreased in all other patients and normalized in 3 patients. No adverse effects appeared in any patient. CONCLUSION: Considering the balance between suppression of disease activity and adverse effects of treatment, mizoribine may be useful for preemptive treatment for patients with ANCA-associated renal vasculitis at high risk for relapse.

Aged↗
PubMed2004

The classification of glomerulonephritis in systemic lupus erythematosus revisited.

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Biopsy↗
PubMed2004

The classification of glomerulonephritis in systemic lupus erythematosus revisited.

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or =50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Humans↗
PubMed2004

Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy.

BACKGROUND: IgA nephropathy is the most common form of glomerulonephritis worldwide. We previously reported a novel form of glomerulonephritis with glomerular IgA deposits following methicillin-resistant Staphylococcus aureus (S. aureus) infection. We investigated the role of S. aureus related antigens in the immunopathogenesis of IgA nephropathy by producing several monoclonal antibodies against S. aureus surface antigens and determining the epitopes of deposited antigens in patients with IgA nephropathy. METHODS: Cell membrane proteins were isolated from cultured S. aureus. Mouse monoclonal antibodies against these proteins were generated, and their target epitopes were determined by antibody affinity chromatography and amino acid sequence analysis, and by monoclonal antibody screening of Escherichia coli clones transfected with plasmids from the Lambda S. aureus Genomic Library. Renal biopsy specimens from 116 patients with IgA nephropathy and 122 patients with other forms of renal disease were examined for glomerular antigen depositions by immunofluorescence microscopy. RESULTS: . The major antigen recognized by monoclonal antibodies against S. aureus cell membrane was identified as the S. aureus cell envelope antigen designated 'probable adhesin' (ACCESSION AP003131-77, Protein ID; BAB41819.1). In 68.1% (79/116) of renal biopsy specimens from patients with IgA nephropathy, S. aureus cell envelope antigen was localized in the glomeruli, and the data confirmed that S. aureus cell envelope antigen was co-localized with IgA antibody in the glomeruli. No deposition of this antigen was detected in the glomeruli of patients with non-immune complex deposit forms of glomerulonephritis. CONCLUSION: S. aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy.

Amino Acid Sequence↗
PubMed2004

Cationic charge-preferential IgG reabsorption in the renal proximal tubules.

BACKGROUND: The brush border of the renal proximal tubules has a polyanionic charge. Since immunoglobulin G (IgG) molecules have a wide range of charge diversity, reabsorption of urinary IgG molecules are supposed to be influenced by the electrostatic interaction. METHODS: Charge diversity of serum and urinary IgG molecules in patients with various renal diseases (N= 12) and premature neonates (N= 3) were analyzed by isoelectric focusing and Immunoblotting. RESULTS: In patients with glomerular diseases, urinary IgG was solely composed of neutral and anionic IgG, whereas that of the cationic part (isoelectric point >8) was not observed. By contrast, in patients with proximal tubular diseases (Dent's disease and idiopathic Fanconi syndrome), the proportion of the cationic IgG was similar to that of serum IgG. In addition, the cationic part of IgG in the urine was found in the neonates with a gestational age of 28 and 31 weeks, but not found in those of 35 weeks. CONCLUSION: The results suggest that renal proximal tubules reabsorb the urinary IgG in a cationic preferential way, and this mechanism requires renal maturation.

Adolescent↗
PubMed2003

Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm.

BACKGROUND: Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)-2 in VSMC apoptosis was studied in MS aneurysm. METHODS AND RESULTS: Aneurysm tissue was obtained from patients undergoing surgery (MS: 4 M, 1 F, age 27-45 years; BAV: 3 M, 2 F, age 28-65 years). Normal aorta from subjects with nonaneurysm disease was also collected (4 M, 1 F, age 23-93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution of fibrillin, fibronectin, and tenascin. Western blot showed no increase in expression of fibrillin, fibronectin, or tenascin in MS or BAV VSMC and increased expression of MMP-2 in MS VSMCs. There was 4-fold increase in loss of cultured VSMC incubated in serum-free medium for 24 hours in both MS (27+/-8%) and BAV (32+/-14%) compared with control (7+/-5%). CONCLUSIONS: In MS and BAV there is alteration in both the amount and quality of secreted proteins and an increased degree of VSMC apoptosis. Up-regulation of MMP-2 might play a role in VSMC apoptosis in MS VSMC. The findings suggest the presence of a fundamental cellular abnormality in BAV thoracic aorta, possibly of genetic origin.

Adult↗
PubMed2003

Localization of intercellular adherens junction protein p120 catenin during podocyte differentiation.

To reveal the role of cadherin complex in podocyte differentiation, the present study describes the localization of the cadherin complex, including p120 catenin (p120ctn), in the developing and in the aminonucleoside nephrosis (PAN nephrosis) rat kidney, by immunofluorescence microscopy and immunogold electron microscopy. p120ctn and beta-catenin were co-localized at the apical part of lateral cell membranes in presumptive podocytes of the S-shaped body, and their localization shifted to the basal margin of lateral cell membranes in the capillary loop stage. There was no expression of the cadherin complex at the slit diaphragm, the intercellular junction of mature podocytes. After the regression of the podocyte junctional structure in PAN nephrosis, the cadherin complex was not re-expressed. The dynamic changes in the localization of the cadherin complex suggest that the it plays an important role during podocyte differentiation, including the rearrangement of the intercellular junction and the formation of the slit diaphragm.

Adherens Junctions↗
PubMed2003

Simultaneous development of lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma--analyses of the clonal relatedness by sequencing CDR3 in immunoglobulin heavy chain genes.

A 75-yr-old male simultaneously having lymphoplasmacytic lymphoma (LPL) and diffuse large B-cell lymphoma (DLBCL) is presented. He had manifested with lumbago, high-grade fever, and confusion. Physical examination on admission showed disorientation and severe back pain. There were neither lymphadenopathy nor hepatosplenomegaly. Routine laboratory tests showed moderate pancytopenia, hypercalcemia (serum calcium, 15.9 mg/dL), IgM lambda-type monoclonal gammopathy (IgG, 405 mg/dL; IgA, 42 mg/dL; and IgM, 2023 mg/dL), and lambda-type Bence-Jones protein in the urine (0.8 g/d). Bone marrow biopsy showed the clusters of surface lambda-positive small-sized mature-appearing lymphoplasmacytoid cells. Bone survey and computed tomographic scan showed multiple osteolytic lesions and a tumor involving the third lumbar spine (L3). An open biopsy of the L3 tumor showed diffuse proliferation of CD20- and lambda-positive large cells. We thus diagnosed the patient as simultaneously having LPL and DLBCL. Although the combination chemotherapy was at least partially effective, he died of bacteremia and organ failure after three courses of chemotherapy. To clarify the clonal relatedness between LPL and DLBCL, we analyzed the sequences of the complementarity-determining region 3 in immunoglobulin heavy-chain genes. The data showed that LPL and DLBCL in the present patient originated from two independent clones.

Aged↗
PubMed2003

Variable expression of podocyte-related markers in the glomeruloid bodies in Wilms tumor.

Several podocyte-related markers are organized to express in glomerular differentiation. However, whether expression of them is virtually synchronized and a reliable indicator of the state of differentiation is unknown. The present study investigated, by immunohistochemistry, the divergent expression of several podocyte markers in the improperly differentiated glomeruloid bodies from four cases of Wilms tumors. The glomeruloid bodies were classified into immature (IGB) or mature forms (MGB) based on morphology and epithelial features. Podocytes in IGB expressed WT1, synaptopodin, podocalyxin, and nephrin, and their expression was stronger in MGB. In contrast, Pax2 was strong in IGB and diminished in MGB. p27 was first expressed in MGB. The expression pattern in each molecule mimics normal glomerulogenesis. Podocytes in MGB showed persistent expression of bcl-2 and cytokeratin with synaptopodin, podocalyxin, and nephrin by serial section, a finding unusual for normal glomerulogenesis. Moreover, parietal cells in MGB also occasionally expressed these podocyte markers. The ultrastructure revealed that podocytes in MGB showed tight junctions without foot process formations, which indicated incomplete differentiation. These results suggest that a set of podocyte differentiation markers are occasionally diversely expressed, and raise the possibility that expression of these markers is insufficient to determine the state of terminal differentiation in podocytes.

Biomarkers, Tumor↗
PubMed2003

Pathogenesis of human renal dysplasia: an alternative scenario to the major theories.

Among the various congenital anomalies of the kidney and urinary tract (CAKUT), renal dysplasia may deserve the closest attention due to its frequency and clinical severity. However, the pathogenesis of this disease is still not well known. It is believed that renal dysplasia is caused by a nephron induction deficit due to ampullary inactivity, or an abnormal budding of the ureteric bud from the mesonephric duct. Renal dysplasia is frequently associated with urinary tract obstruction, suggesting an alternative mechanism whereby urinary retention causes abnormal kidney development. Multicystic dysplastic kidney (MCDK) and obstructive renal dysplasia (ORD) are two different phenotypes of dysplasia associated with urinary tract obstruction. From detailed morphological studies using fetal dysplastic kidneys, nephron induction with filtrating function occurs before cysts are formed. Moreover, three-dimensional reconstruction of dysplastic nephrons showed that cysts developed in the once-induced nephrons as the result of fluid retention in both MCDK and ORD. In utero urinary tract obstruction may cause urine retention in functioning nephrons and lead to multiple cyst formation in the nephrogenic zone. These findings are common to MCDK and ORD, although there may be a difference in the obstruction site. Expansion of cysts with tubular dilatation (cysts) disturbs the subsequent nephrogenesis by the deregulated expression of growth and transcription factors, and may contribute to the misdevelopment of fetal kidneys.

DNA-Binding Proteins↗
PubMed2003

Connective tissue growth factor participates in scar formation of crescentic glomerulonephritis.

Glomerular crescents are a major determinant of progression in various renal diseases. Some types of growth factors are known to be involved in the evolution of crescents and the subsequent scar formation. Although glomerular parietal epithelial cells (PECs) are the major component of cellular crescents, the influence of growth factors on PECs is unknown. We performed immunohistochemical studies and in situ hybridization to examine alterations in connective tissue growth factor (CTGF) expression and to identify CTGF-synthesizing cells in crescents in the crescentic glomerulonephritis model of Wistar Kyoto rats. In addition, we examined the roles of fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta, and CTGF in cell proliferation and matrix synthesis in an established rat PEC cell line (PEC line). In an acute phase of rat crescentic glomerulonephritis, a major component of the crescents were macrophages, which did not express CTGF mRNA. However, in the advanced phase, crescents strongly expressed CTGF mRNA and the epithelial marker pan-cadherin but did not express the macrophage marker ED1, suggesting that PECs synthesized the CTGF. In the PEC line, FGF-2 predominantly promoted [(3)H]thymidine incorporation compared with PDGF-BB. Both TGF-beta and PDGF-BB strongly stimulated extracellular matrix synthesis in association with up-regulation of endogenous CTGF, but TGF-beta showed a predominant role. FGF-2 had a minor effect on it. In addition, blockade of endogenous CTGF using an antisense oligodeoxynucleotide significantly attenuated both TGF-beta- and PDGF-BB-induced extracellular matrix synthesis. These results suggest that several growth factors promote cell proliferation and matrix production in PECs. CTGF-mediated matrix production via the TGF-beta or PDGF-BB pathway in PECs may, in part, play a role in the progression of scar formation in crescents.

Animals↗