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Biomedical subjects

H Wakui

Publications and source records attributed to H Wakui.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of the NPHP genes in two Japanese patients with suspected sporadic juvenile or adolescent nephronophthisis.

BACKGROUND: Mutations in 3 genes (NPHP1, NPHP3 and NPHP4) have been identified in patients with juvenile or adolescent nephronophthisis (NPHP) without extrarenal involvement, mainly in patients from western countries. In this study, we analyzed mutations in the NPHP genes of 2 Japanese patients with suspected sporadic juvenile or adolescent NPHP without extrarenal involvement. METHODS: A renal biopsy was performed in the 2 patients. Genomic DNA was prepared from peripheral blood mononuclear cells of the patients and their family members. The above NPHP genes were examined by deletion analysis or direct automated sequencing of polymerase chain reaction-amplified DNA products. RESULTS: Histological findings in the patients were compatible with those of NPHP. In 1 patient, we identified a novel deletion mutation including about half of exons of the NPHP1 gene. In another patient, there was no mutation in the NPHP genes examined. CONCLUSIONS: We found a novel NPHP1 deletion in 1 patient. To our knowledge, this is the second Japanese NPHP case in which genetic diagnosis was made.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Increased serum levels of S100A12 in patients with MPO-ANCA-associated glomerulonephritis.

BACKGROUND: Increased serum levels of S100A12, a proinflammatory protein secreted by activated neutrophils, have recently been shown in patients with active inflammatory diseases, such as rheumatoid arthritis and Kawasaki disease. In this study, we investigated serum levels of S100A 12 in patients with small-vessel vasculitis, myeloperoxidase anti-neutrophil cytoplasmic antibodies- (MPO-ANCA) associated pauci-immune glomerulonephritis. METHODS: Serum S100A12 concentrations were measured by a sandwich enzyme-linked immunosorbent assay (ELISA) in 46 patients with MPO-ANCA-associated glomerulonephritis and 29 healthy controls. We analyzed correlations between serum S100A12 levels and a clinical index of vasculitis activity, the Birmingham Vasculitis Activity Score (BVAS), various laboratory parameters, and pathological activity scores in the patients. We also analyzed changes of serum S100A12 levels in 10 patients after treatment. RESULTS: ELISA showed about 4-fold higher levels of serum S100A12 in patients with MPO-ANCA-associated glomerulonephritis than healthy controls. Serum S100A12 levels correlated with the BVAS scores, the peripheral white blood cell count, levels of serum C-reactive protein and creatinine, and pathological activity scores in the patients, but did not correlate with serum MPO-ANCA titers. Serum S100A12 levels after treatment decreased in all the 10 patients examined. CONCLUSION: We demonstrated that increased serum S100A12 levels correlate with clinical, laboratory and pathological parameters of disease activity in patients with MPO-ANCA-associated glomerulonephritis. Serum S100A12 level may be one of the useful markers of disease activity in MPO-ANCA-associated glomerulonephritis.

Adolescent↗
PubMed2004

A nonsense mutation (R220X) in the alpha-galactosidase A gene causes typical Fabry disease in both genders.

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). Chronic renal failure is an important cause of death in patients with Fabry disease. We report on patients with Fabry disease (a hemizygous male and his mother) due to a nonsense mutation (R220X) in the alpha-Gal A gene. METHODS: The proband, a 41-year-old man, and his 71-year-old mother presented with renal and cardiac manifestations of Fabry disease. Histological examination and molecular analysis of the alpha-Gal A gene were performed. RESULTS: Typical histological findings of Fabry disease were observed in a renal biopsy specimen from the proband and in renal and myocardial necropsy specimens from the mother. Sequencing of a full-length alpha-Gal A cDNA from the proband indicated a C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X). Examination of genomic alpha-Gal A DNA revealed that the proband was a hemizygote and the mother was a heterozygous carrier for the mutation. CONCLUSION: This is the first detailed report of family members with Fabry disease due to a nonsense mutation (R220X) in the alpha-Gal A gene. Our study indicates that this mutation causes the typical disease in both genders.

Adult↗
PubMed2003

Amyloid A-type renal amyloidosis in a patient with sarcoidosis: report of a case and review of the literature.

A 53-year-old man developed chronic renal failure during a protracted course of sarcoidosis. A renal biopsy showed Congo red-positive homogenous deposits in the subendothelial space of glomerular capillary walls and arterial walls. On electron microscopy, amyloid fibrils were observed in the deposits. Immunohistochemistry showed positive staining for amyloid A (AA) protein. Treatment with prednisolone resulted in poor response, followed by progressive deterioration of renal function requiring hemodialysis. To our knowledge, there are 5 cases with histologically proven renal amyloidosis accompanied by sarcoidosis. Prognosis in these patients is extremely poor. AA-type amyloidosis should be considered as a rare renal complication in the setting of long-standing sarcoidosis.

Amyloidosis↗
PubMed2001

Extremely short small bowel induces focal tubulointerstitial fibrosis.

BACKGROUND: Arginine becomes an essential amino acid after massive resection of the small bowel as a result of decreased biosynthesis of citrulline in the remaining small bowel. It is also reported that nitric oxide (NO) is synthesized from l-arginine by NO synthase (NOS), and NO is involved in the regulation of blood flow in the kidney. The authors observed a patient with an extremely short small bowel, showing focal tubulointerstitial fibrosis. The experiment was designed to clarify whether massive small bowel resection (SBR) produces focal tubulointerstitial fibrosis in the kidney. METHODS: An experimental study was performed using 4-week-old rats with 90% proximal SBR either with or without arginine supplementation for 6 weeks after surgery. RESULTS: In rats without arginine supplementation, low plasma levels of citrulline and arginine increased urinary excretion of orotate, and focal tubulointerstitial fibrosis was observed 6 weeks after 90% SBR. The data from plasma amino acid chromatography and increased excretion of urinary orotate suggested the presence of arginine deficiency. The kidney pathology was similar to that of our patient. Rats with arginine supplementation after 90% SBR and pair-fed control rats without 90% SBR showed almost normal glomeruli and tubulointerstitium. CONCLUSIONS: Experimental study strongly suggests that arginine deficiency causes focal tubulointerstitial fibrosis in the kidney after massive SBR.

Animals↗
PubMed2001

Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140.

Proteins belonging to the 14--3-3 family interact with various regulatory proteins involved in cellular signaling, cell cycle regulation, or apoptosis. 14--3-3 proteins have been suggested to act by regulating the cytoplasmic/nuclear localization of their target proteins or by acting as molecular scaffolds or chaperones. We have previously shown that overexpression of 14--3-3 enhances the transcriptional activity of the glucocorticoid receptor (GR), which is a member of the nuclear receptor family. In this study, we show that 14--3-3 interacts with the nuclear receptor corepressor RIP140. In transfection assays, RIP140 antagonizes 14--3-3- enhanced GR transactivation. Using colocalization studies we demonstrate that 14--3-3 can export RIP140 out of the nucleus and, interestingly, can also change its intranuclear localization. Moreover, we also observed that 14--3-3 can bind various other nuclear receptors and cofactors. In summary, our findings suggest that 14--3-3-mediated intracellular relocalization of the GR corepressor RIP140 might be a novel mechanism to enhance glucocorticoid responsiveness of target genes. They furthermore indicate a more general role for 14--3-3 protein by influencing the nuclear availability of nuclear receptor-associated cofactors.

14-3-3 Proteins↗
PubMed2000

The pro-apoptotic protein death-associated protein 3 (DAP3) interacts with the glucocorticoid receptor and affects the receptor function.

The yeast two-hybrid system was used to isolate cDNAs encoding proteins that interact with the glucocorticoid receptor (GR) ligand-binding domain in a ligand-dependent manner. One isolated cDNA encoded a fragment of death-associated protein 3 (DAP3), which has been implicated as a positive mediator of apoptosis. In vitro experiments showed that the full-length DAP3 also interacted with GR. The main interaction domain was mapped to the N-terminal region of DAP3 that had previously been shown to function in a dominant-negative fashion, protecting cells from apoptosis. Co-transfection experiments in COS-7 cells showed that DAP3 had a stimulatory effect on the ligand-induced transcriptional activation by GR and also increased the steroid-sensitivity. Furthermore, DAP3 formed a complex with several other nuclear receptors and some basic helix-loop-helix/Per-Arnt-Sim proteins, as well as with heat-shock protein 90 (hsp90) (Arnt is the aryl-hydrocarbon-receptor nuclear translocator, and Per and Sim are the Drosophila proteins Period and Single-minded). The results suggest that DAP3 could have an important role in GR action, possibly by modulating the cytoplasmic GR-hsp90 complex. Since glucocorticoids can induce apoptosis, the pro-apoptotic DAP3 protein may be involved in this function of GR.

Amino Acid Sequence↗
PubMed2000

Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein.

Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive activity. MIZ has been approved in Japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nephritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins involved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor. We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3eta dose dependently in vitro. MIZ also has a stimulatory effect on transcriptional activation by the GR. Our results point to the possibility that one mechanism for the therapeutic effect of MIZ could be to regulate the GR function via 14-3-3 proteins.

14-3-3 Proteins↗
PubMed2000

Disappearance of nodular mesangial lesions in a patient with light chain nephropathy after long-term chemotherapy.

A 64-year-old man developed multiple myeloma (kappa light chain type), nephrotic syndrome, and renal insufficiency in 1993. A renal biopsy showed typical histological findings of light chain nephropathy: nodular glomerulosclerosis with deposition of kappa light chains in the mesangial area and subendothelial space of the glomerular capillary walls. Long-term intermittent MEVP chemotherapy (melphalan, 4 mg/d for 4 days; cyclophosphamide, 100 mg/d for 4 days; vincristine, 1 mg/d; prednisolone, 40 mg/d for 4 days) diminished proteinuria and improved renal function. In April 1999, a follow-up biopsy showed remarkable diminution of nodular lesions and disappearance of kappa light chain deposits. Although the prognosis of light chain nephropathy has been considered poor, long-term successful chemotherapy can clear light chain deposits and restore renal function.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Endocapillary proliferative glomerulonephritis in a patient with parvovirus B19 infection.

A 45-year-old woman developed acute nephritic syndrome after erythema infectiosum. Laboratory data on admission showed decreased serum C3, C4, and CH50 levels and the presence of both immunoglobulin (Ig) M and IgG antibodies to human parvovirus B19 (HPV). A renal biopsy showed diffuse endocapillary proliferative glomerulonephritis. Immunofluorescence microscopy indicated 2+ granular staining for IgG, IgM, and C3 over the mesangial area and along glomerular capillary walls. HPV antigen was also detected in glomeruli by immunohistochemistry. Electron microscopy showed electron-dense deposits in the subendothelial space and the paramesangial area. These findings suggest that immune complex-type glomerulonephritis is caused by glomerular deposition of HPV antigen-antibody complexes in some patients with HPV infection.

Antigen-Antibody Complex↗
PubMed2000

Hemoperitoneum due to acute cytomegalovirus infection in a patient receiving peritoneal dialysis.

A 27-year-old man receiving continuous ambulatory peritoneal dialysis (CAPD) developed high-grade fever, dyspnea, and hemoperitoneum 32 months after the start of CAPD. A chest computed tomograph showed fine reticular shadows in the bilateral lower lung fields. Cytomegalovirus (CMV) antigenemia were detected, and immunoglobulin (Ig) M and IgG antibodies for CMV were also positive. The absolute counts of helper T cells (478/microL) and the ratio of helper T cells/suppressor T cells (0.25) decreased, despite no evidence of hematologic or immunologic diseases, including human immunodeficiency virus (HIV) or human T cell lymphoma virus-1 (HTLV-1) infection, or the use of immunosuppressive drugs. All symptoms, including hemoperitoneum and the ratio of helper T cells/suppressor T cells, improved gradually and spontaneously. Acute and primary cytomegalovirus (CMV) infection induced hemoperitoneum in a patient who was receiving CAPD.

Acute Disease↗
PubMed2000

Simultaneous macroamylasemia and macrolipasemia in a patient with systemic lupus erythematosus in remission.

We report the fourth case of simultaneous macroamylasemia and macrolipasemia. A 39-year-old woman had been treated for systemic lupus erythematosus from 1982 to 1993. She was found to have an unexplained increase in serum amylase and lipase activities since 1996. Immunoprecipitation assay showed that amylase was bound to IgA2-kappa and IgA1-kappa (IgA2 > IgA1), whereas lipase was bound to IgA1-kappa. During a follow-up period up to December 1999, the patient did not develop any additional autoimmune or lymphoproliferative disorders. In the situation of atypical clinical features associated with hyperamylasemia and hyperlipasemia, the possibility of macroenzymes should be considered.

Adult↗
PubMed1999

Mammalian HSP60 is a major target for an immunosuppressant mizoribine.

It has been reported that immunosuppressant cyclosporin A or FK506 binds to immunophilins in the cell and that these immunophilins make a complex with molecular chaperones HSP70 or HSP90. Although mizoribine has been used clinically as an immunosuppressant, immunophilins of the agent have not yet been fully understood. We investigated their specific binding proteins using mizoribine affinity column chromatography and porcine kidney cytosols. By increasing mizoribine in the eluant from the column, two major proteins (with molecular masses of 60 and 43 kDa) were detected by SDS-polyacrylamide gel electrophoresis. Based on the amino acid sequence analysis of these proteins, 60- and 43-kDa mizoribine-binding proteins were identified with HSP60 and cytosolic actin, respectively. A considerable amount of actin was also eluted from the affinity column by nucleotides, but a very low quantity of HSP60 was eluted under the same conditions. On the other hand, HSP60 was eluted as a major protein in the eluant that was eluted preferentially, with nucleotide followed by mizoribine. Actin was also detected in the eluant, but the quantity of the protein was very low. These results indicated that HSP60 has high affinity to mizoribine, and the interaction was also observed on surface plasmon resonance analysis. Although HSP60 or GroE facilitated refolding of citrate synthase in vitro, mizoribine interfered with the chaperone activity of HSP60. On different types of mizoribine affinity columns, HSP60 or actin recognized the NH(2) group of mizoribine, and this group may be a functional group of the agent.

Amino Acid Sequence↗
PubMed1999

A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90.

The 90-kDa heat shock protein (HSP90) acts as a specific molecular chaperone in the folding and regulates a wide range of associated proteins such as steroid hormone receptors. It is known that HSP90 possesses two different chaperone sites, both in the N- and C-domains, and that the chaperone activity of HSP90 is blocked by binding of geldanamycin (GA) to the N-domain, the same as the ATP-binding site. Here we show that Cisplatin [cis-diamminedichloroplatinum (II), CDDP], an antineoplastic agent, associates with HSP90 and reduces its chaperone activity. In order to analyse the binding proteins, bovine brain cytosols were applied to a CDDP-affinity column and binding proteins were eluted by CDDP. In the elutants, only 90-kDa protein bands were detected on SDS/PAGE, and the protein was cross-reacted with the anti-HSP90 antibody on immunoblotting. No protein bands were detected in the elutants from the control column on SDS/PAGE. These results indicated that CDDP has a high affinity for HSP90. On CD spectrum analysis, the binding of CDDP to HSP90 resulted in a conformational change in the protein. Although HSP90 inhibited the aggregation of citrate synthase as a molecular chaperone in vitro, the activity was suppressed almost completely in the presence of CDDP. Mg/ATP has an influence on the chaperone activity to some extent. The CDDP binding region of HSP90 is near the C-terminal which is quite different from the GA-binding site. Our results suggest that the chaperone activity of HSP90 may be inhibited by the binding of CDDP or GA by different mechanisms.

Adenosine Triphosphate↗
PubMed1999

Collagenofibrotic glomerulopathy: a systemic disease.

Collagenofibrotic glomerulopathy is a recently discovered entity that is characterized by massive accumulation of spiraled and frayed collagen fibrils in mesangial and subendothelial areas, and elevated serum levels of procollagen III peptide. We report the autopsy of a patient who received continuous ambulatory peritoneal dialysis (CAPD) therapy for 7 years. Autopsy disclosed that massive accumulation of peculiar collagen fibers was found not only in the kidney, but also in many organs including spleen, liver, myocardium, and thyroid gland. Although the possibility remains that CAPD for 7 years might change or aggravate the deposition of abnormal collagen, the current case suggests a possibility that collagenofibrotic glomerulopathy is a systemic disorder with abnormal metabolism of type III collagen.

Adult↗
PubMed1999

Circulating antibodies against alpha-enolase in patients with primary membranous nephropathy (MN).

MN is characterized by the glomerular deposition of IgG4 immune complexes. This suggests that nephritogenic immune responses in MN are of the Th2 T helper cell type; however, the pathogenesis of MN is still unknown. In this study we examined sera from patients with primary MN for antibodies to renal proteins. A 47-kD protein in both human and porcine renal extracts was found by immunoblotting to react specifically with serum IgG from some patients. This protein was purified from porcine kidney and identified as alpha-enolase on the basis of its partial amino acid sequences. Sera from 87 patients with primary MN, 24 patients with secondary MN (15 rheumatoid arthritis patients, nine systemic lupus erythematosus patients), and 16 healthy subjects were examined by ELISA using purified alpha-enolase. In 60 (69%) patients with primary MN and 14 (58%) patients with secondary MN, the measured optical density values, and hence serum anti-alpha-enolase antibody levels, were greater than the mean + 2 s.d. of healthy subjects. Immunoblot analysis showed that IgG1 or IgG3 was the predominant subclass (Th1 T helper cell type subclass) of antibodies against alpha-enolase in patients with primary and secondary MN. Since circulating antibodies against alpha-enolase have recently been reported in patients with various autoimmune disorders, our results suggest that a number of patients with presumed primary MN may also have abnormalities in Th1 T helper cell-mediated immune responses.

Adolescent↗