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Dive into the research topics where Kazuhide Uemura is active.

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Featured researches published by Kazuhide Uemura.


Journal of Biological Chemistry | 2008

Roles of Pofut1 and O-Fucose in Mammalian Notch Signaling

Mark Stahl; Kazuhide Uemura; Changhui Ge; Shaolin Shi; Yuko Tashima; Pamela Stanley

Mammalian Notch receptors contain 29–36 epidermal growth factor (EGF)-like repeats that may be modified by protein O-fucosyltransferase 1 (Pofut1), an essential component of the canonical Notch signaling pathway. The Drosophila orthologue Ofut1 is proposed to function as both a chaperone required for stable cell surface expression of Notch and a protein O-fucosyltransferase. Here we investigate these dual roles of Pofut1 in relation to endogenous Notch receptors of Chinese hamster ovary and murine embryonic stem (ES) cells. We show that fucosylation-deficient Lec13 Chinese hamster ovary cells have wild type levels of Pofut1 and cell surface Notch receptors. Nevertheless, they have reduced binding of Notch ligands and low levels of Delta1- and Jagged1-induced Notch signaling. Exogenous fucose but not galactose rescues both ligand binding and Notch signaling. Murine ES cells lacking Pofut1 also have wild type levels of cell surface Notch receptors. However, Pofut1–/– ES cells do not bind Notch ligands or exhibit Notch signaling. Although overexpression of fucosyltransferase-defective Pofut1 R245A in Pofut1–/– cells partially rescues ligand binding and Notch signaling, this effect is not specific. The same rescue is achieved by an unrelated, inactive, endoplasmic reticulum glucosidase. Therefore, mammalian Notch receptors require Pofut1 for the generation of optimally functional Notch receptors, but, in contrast to Drosophila, Pofut1 is not required for stable cell surface expression of Notch. Importantly, we also show that, under certain circumstances, mammalian Notch receptors are capable of signaling in the absence of Pofut1 and O-fucose.


Journal of Immunology | 2002

L-MBP is expressed in epithelial cells of mouse small intestine

Kazuhide Uemura; Masako Saka; Tomoaki Nakagawa; Nobuko Kawasaki; Steffen Thiel; Jens C. Jensenius; Toshisuke Kawasaki

The mannan-binding proteins (L-MBP and S-MBP, also denoted MBL-C and MBL-A), mainly produced in liver and existing in liver and serum, play important roles in the innate immunity against a variety of pathogens. Total RNA from mouse tissues were screened for MBP mRNA by RT-PCR. In addition to liver, S-MBP mRNA was detected in lung, kidney, and testis, and L-MBP mRNA was detected in kidney, thymus, and small intestine. Quantitative RT-PCR revealed that the small intestine is a predominant site of extrahepatic expression of L-MBP. Western blotting with polyclonal Abs against rat L-MBP demonstrated this protein in Triton X-100 extracts of the small intestine obtained from mice that had undergone systemic perfusion. Immunohistochemical staining with an mAb against mouse L-MBP and in situ hybridization revealed that L-MBP is selectively expressed in some villous epithelial cells of the small intestine. These findings suggest that L-MBP plays a role in mucosal innate immunity.


International Immunopharmacology | 2001

Recombinant expression of human mannan-binding lectin

Thomas Vorup-Jensen; Esben S. Sørensen; Uffe Birk Jensen; Wilhelm J. Schwaeble; Toshisuke Kawasaki; Yong Ma; Kazuhide Uemura; Nobutaka Wakamiya; Yasuhiko Suzuki; Thomas G. Jensen; Kazue Takahashi; R. Alan B. Ezekowitz; Steffen Thiel; Jens Chr. Jensenius

Mannan-binding lectin (MBL) constitutes an important part of the innate immune defence by effecting the deposition of complement on microbial surfaces. MBL deficiency is among the most common primary immunodeficiencies and is associated with recurrent infections and symptoms of poor immune complex clearance. Plasma-derived MBL has been used in reconstitution therapy but concerns over viral contamination and production capacity point to recombinant MBL (rMBL) as a future source of this protein for clinical use. Natural human MBL is an oligomer of up to 18 identical polypeptide chains. The synthesis of rMBL has been accomplished in several mammalian cell lines, however, the recombinant protein differed structurally from natural MBL. In this, study we compare rMBL produced in myeloma cells, Chinese hamster ovary (CHO) cells, human hepatocytes, and human embryonic kidney (HEK) cells. We report that rMBL structurally and functionally similar to natural MBL can be obtained through synthesis in the human embryonic kidney cells followed by selective carbohydrate affinity chromatography.


AIDS Research and Human Retroviruses | 2002

High Mannose Glycans and Sialic Acid on gp120 Regulate Binding of Mannose-Binding Lectin (MBL) to HIV Type 1

Melanie L. Hart; Mohammed Saifuddin; Kazuhide Uemura; Eric G. Bremer; Brad Hooker; Toshisuke Kawasaki; Gregory T. Spear

Mannose-binding lectin (MBL) is a C-type lectin of the innate immune system that binds to carbohydrates on the surface of certain microorganisms. Previous studies showed that MBL binds to gp120, the envelope glycoprotein of HIV-1. gp120 is extensively glycosylated, with N-linked complex and high mannose carbohydrates accounting for about half of the molecular weight. The objectives of this study were to determine the types of glycans on gp120 important for MBL binding and to determine if alteration of complex glycans with neuraminidase (NA) could enhance the interaction of MBL with virus. Lectin blot analyses revealed that MBL interacted with recombinant gp120 (rgp120) from both T cell-tropic and M-tropic virus strains. Treatment of rgp120 with endoglycosidase H (eH) or endoglycosidase F1 (eF1) abrogated binding of MBL, but did not decrease binding of wheat germ agglutinin indicating that high mannose and/or hybrid N-linked glycans were required for MBL binding. Removal of sialic acids from rgp120 with NA enhanced MBL binding. Treatment of intact virus from T cell lines or primary isolates with eF1 also significantly decreased HIV binding to MBL, while treatment with NA substantially increased binding. Treatment of virus with both eF1 and NA did not decrease binding compared to NA alone suggesting that NA treatment exposed binding sites on gp120 that are not high mannose glycans. These studies provide evidence that MBL binds to HIV via high mannose carbohydrates on gp120 and shows that the interaction of MBL with virus is regulated by sialylation.


Methods in Enzymology | 2003

Antitumor Activity of Mannan-Binding Protein

Tomoaki Nakagawa; Nobuko Kawasaki; Yong Ma; Kazuhide Uemura; Toshisuke Kawasaki

Publisher Summary This chapter investigates the antitumor activity of mannan-binding protein (MBP). MBP has been shown to recognize certain carbohydrate structures expressed on the surfaces of a wide variety of microorganisms, to trigger carbohydrate-mediatedcomplement activation, and to exhibit complement-dependentbactericidal activity. Normal mammalian cells are usually covered with complex oligosaccharides terminating in sialic acids and do not bind MBP. MBP recognizes and binds specifically to oligosaccharide ligands expressed on the surfaces of human tumor cells, including a human colorectal carcinoma cell line– SW1116. The proposed study in the chapter indicated that the recombinant vaccinia virus carrying the human MBP gene exhibits potent growth-inhibiting activity against SW1116 cells transplanted into KSN nude mice when administered by intratumoral or subcutaneous injection. A significant prolongation inthe life-span of tumor-bearing mice resulted from this treatment. This effect appears to be a consequence of local production of MBP,.therefore, a mutant MBP, which had essentially no complementactivating activity, was nearly as active as wild-type MBP. These results indicated that MBP has a hithertoundescribed cytotoxic activity, which was proposed to be termed as MBP-dependent cell-mediated cytotoxicity (MDCC).


Nephron Experimental Nephrology | 2011

Sairei-to Ameliorates Rat Peritoneal Fibrosis Partly through Suppression of Oxidative Stress

Masayuki Kitamoto; Kozue Kato; Akihisa Sugimoto; Hisayo Kitamura; Kazuhide Uemura; Toshiya Takeda; Chunmo Wu; Fumiaki Nogaki; Tatsuya Morimoto; Takahiko Ono

Background: Sairei-to is a herbal prescription originating from traditional Chinese medicine. We conducted an experimental study on rat peritoneal fibrosis to clarify the suppressive mechanisms of sairei-to. Methods: Wistar rats were intraperitoneally injected with chlorhexidine gluconate (CG) every day. Peritoneal specimens were collected after 28 days of CG injection and oral administration of sairei-to. Macrophage infiltration, extracellular matrix accumulation, and angiogenesis were evaluated by immunostaining for ED-1, fibronectin, and CD-31, respectively. To observe oxidative stress in the tissue, 4-hydroxy-2-noneal (HNE) accumulation and plasma levels of superoxide dismutase (SOD) activity were detected. As a candidate of antioxidative components in sairei-to, plasma levels of baicalin were determined by high-performance liquid chromatography. Results: Compared with the disease control group, serum total protein levels were significantly recovered in the sairei-to treatment group. Thickness of the submesothelial compact zone, trichrome-stained area, ED-1-positive cells, fibronectin-staining area, and HNE accumulation were suppressed in the treatment group. Concurrently, decreased plasma levels of SOD activity were recovered by sairei-to treatment. Increased CD-31-positive vessel number and area were also suppressed in the sairei-to group. Baicalin was detected in the plasma samples of the sairei-to group at 0.29 ± 0.11 µg/ml (mean±SEM). Conclusion: These results suggest that sairei-to ameliorates peritoneal fibrosis, partly through suppressing oxidative stress and macrophage infiltration.


Clinical and Experimental Nephrology | 2009

Serofendic acid protects from iodinated contrast medium and high glucose probably against superoxide production in LLC-PK1 cells.

Osamu Kitamura; Kazuhide Uemura; Hisayo Kitamura; Hachiro Sugimoto; Akinori Akaike; Takahiko Ono

BackgroundIt is well known that patients with chronic kidney disease, including diabetic nephropathy, often develop cardiovascular diseases. In case of radiographic procedures, reduced renal function may be deteriorated by the use of iodinated contrast medium (CM). This is known as CM-induced nephropathy. In this study, we have focused on the mechanisms of this type of injury in diabetic nephropathy and the preventive effects of serofendic acid.MethodsWe evaluated the cytotoxicity of CM and high glucose on tubular epithelial cells using an LLC-PK1 cell line, and measured cell viability with an alamarBlue assay. We further evaluated superoxide production levels measured by dihydroethidium. We also examined the protective effects of serofendic acid on cytotoxicity with superoxide production of CM and high glucose.ResultsCM reduced cell numbers in a dose-dependent and time-dependent manner in LLC-PK1 cells. Furthermore, cytotoxicity of CM in diluted concentration was additively influenced by high glucose. CM and high glucose increased superoxide production, which was evaluated by the response to dihydroethidium, and was suppressed by serofendic acid. Cytotoxicity of CM, high glucose, and H2O2 was suppressed by serofendic acid, as well as the suppression by N-acetylcysteine on CM toxicity. Interestingly, the recovery by serofendic acid in H2O2- and high glucose-induced cellular injury was to the basal level, in contrast with the partial recovery from CM-induced injury. Finally, serofendic acid suppressed CM-induced injury and high glucose-induced apoptosis.ConclusionsThese results suggest that CM and high glucose induce cytotoxicity and oxidative stress in LLC-PK1 cells and that serofendic acid protects the injury probably from superoxide generation.


Clinical and Experimental Nephrology | 2005

The Na+-excreting efficacy of indapamide in combination with furosemide in massive edema.

Misa Tanaka; Emi Oida; Keiko Nomura; Fumiaki Nogaki; Atsushi Fukatsu; Kazuhide Uemura; Masatomo Yashiro; Takeshi Kimura; Eri Muso; Takahiko Ono

BackgroundMassive systemic edema is often observed in patients with severe nephrotic syndrome, including diabetic nephropathy. Although furosemide, a loop diuretic, is often administered to these patients, some patients do not respond to this treatment, still showing massive edema.MethodsThe efficacy of indapamide which has a thiazide-like effect on distal convoluted tubules in combination with furosemide, was evaluated in eight patients with massive edema, in regard to both Na+ excretion and diuresis. Indapamide 2 mg was administered once a day, in the morning, to patients in whom it was considered that furosemide treatment of 40–120 mg a day for 1 week was ineffective.ResultsUrinary Na+ excretion was markedly increased, from 83.7 ± 82.2 mEq/day to 140.7 ± 33.8 mEq/day after 1 week of the combination therapy compared with furosemide alone (P < 0.01); urine volume was also increased, from 1070 ± 230 ml to 1359 ± 296 ml after 1 week of the combination therapy (P < 0.05). In this context, body weight was significantly decreased, from 57.2 ± 12.3 kg to 53.4 ± 12.8 kg, after the combination therapy (P = 0.01). Indapamide in combination with furosemide was well tolerated, and no significant changes in serum levels of creatinine and potassium were observed.ConclusionsThis combination therapy appears to be effective in patients with massive edema, as it increased diuresis, and achieved potent Na+ excretion.


Clinical and Experimental Nephrology | 2007

Soluble fibrin formation in the mesangial area of IgA nephropathy

Ning Liu; Noriko Mori; Noriyuki Iehara; Kazuhide Uemura; Atsushi Fukastu; Toru Kita; Michio Matsuda; Takahiko Ono

BackgroundFibrin monomer and its derivatives in blood are found in an early stage of thrombosis. When they are produced in blood, they form complexes with fibrinogen, and they exist as soluble complexes named soluble fibrin (SF). As final insoluble products, cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. To clarify the mechanisms of mesangial SF production and its relationship to XFb deposition in IgA nephropathy (IgAN), an immunohistochemical study was conducted.MethodsNineteen patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure. SF was detected with a monoclonal antibody (IF-43), and factor V was detected with a specific rabbit antibody. The relationships of SF staining to the disease activity index, XFb deposition, and factor V staining was evaluated.ResultsXFb, factor V, and SF were observed in the mesangium in 14, 11, and 8, respectively, of a total of 19 specimens. SF had frequent staining in the proliferating areas, showing a significant relationship to XFb or factor V (P < 0.05). Furthermore, XFb, factor V, and SF depositions were markedly correlated with disease activity (P < 0.001 in each case).ConclusionsThese findings suggest that SF is formed in the mesangial area in active IgA nephropathy accompanied by mesangial proliferation, in particular, in its early stage.


Nephron Experimental Nephrology | 2009

Lipopolysaccharide-triggered acute aggravation of mesangioproliferative glomerulonephritis through activation of coagulation in a high IgA strain of ddY mice.

Makiko Shimosawa; Koji Sakamoto; Yuki Tomari; Kohei Kamikado; Hidetaka Otsuka; Ning Liu; Hisayo Kitamura; Kazuhide Uemura; Fumiaki Nogaki; Noriko Mori; Eri Muso; Haruyoshi Yoshida; Takahiko Ono

Background: The high IgA (HIGA) strain of ddY mice represents an inbred model of IgA nephropathy that shows mesangioproliferative glomerulonephritis with mesangial IgA deposition. In this study, aggravation of glomerulonephritis in HIGA mice through lipopolysaccharide (LPS)-triggered activation of coagulation was investigated. Methods: Twelve-week-old HIGA and BALB/c mice were intraperitoneally injected with LPS twice at an interval of 3 days, and kidney specimens were collected 7 days after the second LPS injection. In an intervention experiment, the factor Xa inhibitor danaparoid was injected intraperitoneally every day for 7 days after the first LPS injection. Results: LPS injection induced macrophage infiltration and cellular proliferation in the mesangium together with fibrin deposition and monocyte chemoattractant protein 1 mRNA expression, as well as antigen deposition of tissue factor, factor V, factor X, and protease-activated receptor 2. These phenomena were obvious in HIGA mice when compared to BALB/c mice. Interestingly, toll-like receptor 4 was intensely expressed in HIGA mice before LPS injection and subsequently decreased. Danaparoid treatment significantly ameliorated proteinuria, cellular proliferation, and fibrin deposition. Conclusions: The present data suggest that tissue factor and factor V induction by LPS may in part accelerate mesangioproliferative glomerulonephritis through activation of factor X and downstream proinflammatory and procoagulant mechanisms.

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