2021/10/20 更新

写真a

オオツカ タダシ
大塚 忠司
OTSUKA Tadashi
所属
医歯学総合病院 腎・膠原病内科 助教
職名
助教
外部リンク

学位

  • 学士(医学) ( 2008年3月   新潟大学 )

研究キーワード

  • 腎臓

  • マクロファージ

研究分野

  • ライフサイエンス / 腎臓内科学

経歴(researchmap)

  • 新潟大学医歯学総合病院   腎膠原病内科   助教

    2020年4月 - 現在

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経歴

  • 新潟大学   医歯学総合病院 腎・膠原病内科   助教

    2020年4月 - 現在

  • 新潟大学   医歯学総合病院 腎・膠原病内科   特任助教

    2017年4月 - 2017年9月

学歴

  • 新潟大学   医学部   医学科

    2002年4月 - 2008年3月

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論文

  • Renal tubular dilation and fibrosis after unilateral ureter obstruction revealed by relaxometry and spin-lock exchange MRI. 国際誌

    Feng Wang, Tadashi Otsuka, Keiko Takahashi, Chikage Narui, Daniel C Colvin, Raymond C Harris, Takamune Takahashi, John C Gore

    NMR in biomedicine   e4539   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We evaluated the use of quantitative MRI relaxometry, including the dispersion of spin-lock relaxation with different locking fields, for detecting and assessing tubular dilation and fibrosis in a mouse model of unilateral ureter obstruction (UUO). C57BL/6 J and BALB/c mice that exhibit different levels of tubular dilation and renal fibrosis after UUO were subjected to MR imaging at 7 T. Mice were imaged before UUO surgery, and at 5, 10 and 15 days after surgery. We acquired maps of relaxation rates and fit the dispersion of spin-lock relaxation rates R1ρ at different locking fields (frequencies) to a model of exchanging water pools, and assessed the sensitivity of the derived quantities for detecting tubular dilation and fibrosis in kidney. Histological scores for tubular dilation and fibrosis, based on luminal space and positive fibrotic areas in sections, were obtained for comparison. Histology detected extensive tubular dilation and mild to moderate fibrosis in the UUO kidneys, in which enlargement of luminal space, deposition of collagen, and reductions in capillary density were observed in the cortex and outer stripe of the outer medulla. Relaxation rates R1 , R2 and R1ρ clearly decreased in these regions of UUO kidneys longitudinally. While R1 showed the highest detectability to tubular dilation and overall changes in UUO kidneys, Sρ , a parameter derived from R1ρ dispersion data, showed the highest correlation with renal fibrosis in UUO. While relaxation parameters are sensitive to tubular dilation in UUO kidneys, Sρ depends primarily on the average exchange rate between water and other chemically shifted resonances such as hydroxyls and amides, and provides additional specific information for evaluating fibrosis in kidney disease.

    DOI: 10.1002/nbm.4539

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  • Lipoprotein modulation of proteinuric renal injury. 国際誌

    Yohei Tsuchida, Jianyong Zhong, Tadashi Otsuka, Anna Dikalova, Ira Pastan, G M Anantharamaiah, MacRae F Linton, Patricia G Yancey, T Alp Ikizler, Agnes B Fogo, Haichun Yang, Valentina Kon

    Laboratory investigation; a journal of technical methods and pathology   99 ( 8 )   1107 - 1116   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    High-density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain to renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, and apoAI mimetic (L-4F), and the in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro, primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis, and the underlying signaling pathway were assessed. In vivo, we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25+) mice, which express human CD25 on podocytes. Podocyte injury was induced by using immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25+:apoE-/- mice, was generated by mating apoE-deficient (apoE-/-) mice with NEP25+ mice. Animals received L-4F or control vehicle. Renal function, podocyte injury, and atherosclerosis were assessed. PAN reduced podocyte viability, migration, and increased ROS production, all significantly lessened by apoAI, HDL, and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/signal transducers and activators of transcription 3. In NEP25+ mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25+:apoE-/- mice had more atherosclerosis than non-proteinuric apoE-/- mice, and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL, and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be a novel candidate to lessen podocyte damage and its complications.

    DOI: 10.1038/s41374-019-0253-6

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  • Kidney morphological parameters measured using noncontrast-enhanced steady-state free precession MRI with spatially selective inversion recovery pulse correlate with eGFR in patients with advanced CKD.

    Tadashi Otsuka, Yoshikatsu Kaneko, Yuya Sato, Ryohei Kaseda, Ryuji Aoyagi, Suguru Yamamoto, Shin Goto, Ichiei Narita

    Clinical and experimental nephrology   22 ( 1 )   45 - 54   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: It is well known that atrophic renal changes are associated with chronic kidney disease (CKD) progression, but conventional diagnostic imaging methods such as noncontrast-enhanced computed tomography and magnetic resonance imaging (MRI) have been insufficient for precisely assessing kidney function because they cannot clearly distinguish between the medulla and cortex. Hence, here we used noncontrast-enhanced steady-state free precession (SSFP) MRI with a spatially selective inversion recovery (IR) pulse to improve visibility for renal corticomedullary differentiation and evaluated the association between morphological parameters and kidney function in patients with CKD. METHODS: Kidney corticomedullary contrast ratio, cortical and medullary areas, and minimal cortical thickness of 107 patients with CKD G1-G5 were measured using SSFP MRI with a spatially selective IR pulse and the association between these morphological parameters and kidney function were evaluated. RESULTS: Corticomedullary contrast ratio was significantly improved on SSFP MRI compared with conventional in-phase T1-weighted gradient-echo MRI and positively correlated with estimated glomerular filtration ratio (eGFR), raw eGFR, and 24-h creatinine clearance. The medullary and cortical areas and minimal cortical thickness also positively correlated with those of kidney functional markers and the age. In patients with CKD and diabetes mellitus (DM), the correlation coefficients between raw eGFR and morphological parameters were higher than those in patients without DM, while minimal cortical thickness was larger in CKD patients with DM with a raw eGFR ≥ 45 mL/min. CONCLUSION: Kidney morphological parameters measured with SSFP MRI were clearly correlated with kidney function in patients with CKD, including those with advanced kidney dysfunction.

    DOI: 10.1007/s10157-017-1413-x

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  • An Autopsy Case of Mesenteric Panniculitis with Massive Pleural Effusions. 国際誌

    Hiroshi Kobayashi, Kenji Notohara, Tadashi Otsuka, Yuka Kobayashi, Masuo Ujita, Yuuki Yoshioka, Naomasa Suzuki, Ryuji Aoyagi, Riuko Ohashi, Toshimitsu Suzuki

    The American journal of case reports   19   13 - 20   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND Mesenteric panniculitis (MP) is an idiopathic chronic inflammatory condition of the mesentery. The main symptoms include abdominal pain, abdominal distention, weight loss, fever, nausea, and vomiting. The patients also present with chylous ascites in 14% of the cases and chylous pleural effusion (CPE) in very rare occasions. Despite the previous view of excellent prognosis of MP, two recent papers reported several fatal cases. However, there are still only a few autopsy case reports that describe the macroscopic and histological details of MP cases. CASE REPORT The patient was an 81-year-old Japanese woman. She complained of edema of her lower legs and face, general fatigue, and dyspnea. She was overweight and had type 2 diabetes (T2D). Computerized tomography (CT) demonstrated massive bilateral pleural effusions, with mild pericardial effusion and mild ascites. There was no pulmonary, cardiac or hepatic condition to explain the effusions. However, MP was suspected based on her CT. She gradually deteriorated into respiratory failure. The autopsy revealed CPEs (left 1,300 mL, right 1,400 mL) and MP in the mesentery of the small intestine. Neither neoplasia nor inflammatory conditions other than MP were detected. CONCLUSIONS In rare occasions, patients with MP present with CPE or chylothorax. We thought that a possible mechanism of the CPEs was a diaphragmatic defect. We suspected that being overweight and T2D had an etiological relationship with MP in our patient's case. Adipose tissue of the mesentery is the main focus of MP. We believed that MP would be the best umbrella term of the many synonyms.

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  • Prolactin Upregulates Female-Predominant P450 Gene Expressions and Downregulates Male-Predominant Gene Expressions in Mouse Liver. 国際誌

    Yuya Sato, Yoshikatsu Kaneko, Takamasa Cho, Kei Goto, Tadashi Otsuka, Suguru Yamamoto, Shin Goto, Hiroki Maruyama, Ichiei Narita

    Drug metabolism and disposition: the biological fate of chemicals   45 ( 6 )   586 - 592   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Prolactin is a polypeptide hormone with over 300 separate biologic activities. Its serum level is increased during pregnancy and lactation, and it has been reported that pregnancy and lactation affect drug and steroid metabolism in mice and humans. Several studies reported that pregnancy or lactation influences liver cytochrome P450 (P450) expression and its activity, affecting the biosynthesis of steroids and xenobiotics through growth hormone or sex hormones; however, the role of prolactin as the regulator of liver P450 expression has not been elucidated so far. In the present study, we focused on prolactin as the regulator of expression of liver sex-predominant genes, including P450s. To investigate the role of prolactin in the hepatic gene expressions, pCAGGS expression vector containing mouse prolactin cDNA was transfected by hydrodynamic injection into both male and female mice. Hyperprolactinemia phosphorylated signal transducer and activator of transcription 5 in the liver and augmented female mouse liver mRNA expression of Cyp3a16, Cyp3a41, Cyp3a44, Cyp2b9, and prolactin receptor genes, whose expressions were female-predominant in hepatocytes. Moreover, liver expression of male-predominant genes such as Cyp2d9, Cyp7b1, Mup1, and Alas2 were reduced in male mice with hyperprolactinemia. The serum levels of conventional regulators of hepatic gene expressions, growth hormone, and testosterone were not affected by hyperprolactinemia. We demonstrated that prolactin upregulated female-predominant genes in female mice and downregulated male-predominant genes in male mice. We conjecture that higher concentration of prolactin would alter steroid and xenobiotic metabolisms by modulating hepatic P450 gene expressions during pregnancy and lactation.

    DOI: 10.1124/dmd.116.074658

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  • Leptin deficiency down-regulates IL-23 production in glomerular podocytes resulting in an attenuated immune response in nephrotoxic serum nephritis. 国際誌

    Kei Goto, Yoshikatsu Kaneko, Yuya Sato, Tadashi Otsuka, Suguru Yamamoto, Shin Goto, Keiko Yamamoto, Tadashi Yamamoto, Hiroshi Kawachi, Michael P Madaio, Ichiei Narita

    International immunology   28 ( 4 )   197 - 208   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Leptin, one of the typical adipokines, is reported to promote Th17 cell responses and to enhance production of proinflammatory cytokines. To clarify the role of leptin in the regulation of the IL-23/IL-17 axis and the development of kidney disease, we used a murine model of nephrotoxic serum (NTS) nephritis (NTN). Sheep NTS was administered in wild-type C57BL/6J mice and food-restricted, leptin-deficient C57BL/6J-ob/ob(FR-ob/ob) mice after preimmunization with sheep IgG. The profile of mRNA expression relevant to T helper lymphocytes in the kidneys was analyzed by quantitative real-time PCR (qRT-PCR). Cultured murine glomerular podocytes and peritoneal exudate macrophages (PEMs) were used to investigate the direct effect of leptin on IL-23 or MCP-1 production by qRT-PCR. Kidney injury and macrophage infiltration were significantly attenuated in FR-ob/obmice 7 days after NTS injection. The Th17-dependent secondary immune response against deposited NTS in the glomeruli was totally impaired in FR-ob/obmice because of deteriorated IL-17 and proinflammatory cytokine production including IL-23 and MCP-1 in the kidney. IL-23 was produced in glomerular podocytes in NTN mice and cultured murine glomerular podocytes produced IL-23 under leptin stimulation. MCP-1 production in PEMs was also promoted by leptin. Induction of MCP-1 expression was observed in PEMs regardless of Ob-Rb, and the leptin signal was transduced without STAT3 phosphorylation in PEMs. Leptin deficiency impairs the secondary immune response against NTS and down-regulates IL-23 production and Th17 responses in the NTN kidney, which is accompanied by decreased MCP-1 production and macrophage infiltration in the NTN kidney.

    DOI: 10.1093/intimm/dxv067

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  • Effect of textured eye drop bottles on the photostability of pranoprofen 0.1% ophthalmic solution. 国際誌

    Kinya Iwatsuka, Katsuhiro Inada, Hiroki Ueoka, Tadashi Otsuka, Masaki Maeda, Masazumi Yamaguchi, Shin-ichi Yasueda

    Drug development and industrial pharmacy   41 ( 9 )   1526 - 31   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CONTEXT: Ophthalmic solutions are usually filled in a plastic bottle due to its durability and disposability. In Japan, photostability is one of the concerns for the quality control because an eye drop bottle must be a transparent container. OBJECTIVE: The present work studied the effect of textured eye drop bottles on its light blocking to improve the photostability of ophthalmic solutions. MATERIALS AND METHODS: We investigated the photostability of Pranoprofen ophthalmic solution filled in a variety of textured eye drop bottles. Pranoprofen content was analyzed by high-performance liquid chromatography and surface structure of textured eye drop bottles was evaluated by transmittance, calculated average roughness (Ra) and haze intensity. RESULTS: We observed that eye drop bottle which had greater than Ra value of 1.0 µm and haze intensity 62% clearly showed photostability improvement. CONCLUSIONS: This report is the first one which shows that photostability of ophthalmic solution is improved by using textured eye drop bottle. Moreover, this approach is a simple and effective method to improve the photostability. This method is available for not only various ophthalmic applications but also other liquid pharmaceuticals or food products.

    DOI: 10.3109/03639045.2014.971028

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  • Upregulation of prolactin receptor in proximal tubular cells was induced in cardiac dysfunction model mice.

    Yohei Tsuchida, Yoshikatsu Kaneko, Tadashi Otsuka, Kei Goto, Akihiko Saito, Keiko Yamamoto, Tadashi Yamamoto, Ichiei Narita

    Clinical and experimental nephrology   18 ( 1 )   65 - 74   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: In order to clarify the interaction between cardiac dysfunction and sodium homeostasis in the kidney, we used a murine model of cardiac dysfunction and investigated the effect on sodium transporters in renal tubular cells. METHODS: Cardiac function was deteriorated by abdominal aortic banding, and the gene expression of sodium transporters in the kidneys was evaluated by real-time RT-PCR and compared with that in the kidneys of control mice. RESULTS: Gene expression of all three variants of the murine prolactin receptor was enhanced by aortic banding. Upregulated prolactin receptor was distributed in the proximal tubular cells of the pars recta in the deep inner cortex and the outer stripe of the outer medulla. Prolactin has been reported to be a natriuretic hormone that inhibits proximal tubular Na(+)/K(+)-ATPase activity, resulting in reduced sodium reabsorption and the acceleration of natriuresis. Inhibition of endogenous prolactin secretion by bromocriptine administration decreased the urine sodium excretion in both aortic banding and control mice. On the other hand, excess exogenous prolactin administration enhanced urine potassium excretion in aortic banding mice. Furthermore, a high-sodium diet accelerated urinary sodium excretion, which was also significantly decreased by inhibition of endogenous prolactin secretion in aortic banding mice. CONCLUSION: We reported that the prolactin receptor was upregulated by aortic banding treatment. Prolactin-prolactin receptor interaction in the proximal tubular cells of the pars recta should involve a different mechanism of kaliuresis other than inhibition of Na(+)/K(+)-ATPase.

    DOI: 10.1007/s10157-013-0820-x

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  • Integrin α1/β1 and α2/β1 as a receptor for IgA1 in human glomerular mesangial cells in IgA nephropathy. 国際誌

    Yoshikatsu Kaneko, Tadashi Otsuka, Yohei Tsuchida, Fumitake Gejyo, Ichiei Narita

    International immunology   24 ( 4 )   219 - 32   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA1 and galactose-deficient IgA1 is expected to play a pathogenic role. However, the identity of the receptor for IgA1 is still controversial. Hence, the aim of this study was to explore the receptor for galactose-deficient IgA1. Human monoclonal IgA1 was treated with exoglycosidase and FITC-conjugated control, asialo- and agalactosyl-IgA1 was used as a probe to detect the receptor in cultured human mesangial cells. Tumor necrosis factor-α or transforming growth factor-β1 treatment accelerated IgA1-binding on mesangial cells, and these effects were diminished by the addition of dexamethasone, whereas these changes were not dependent on galactose-deficiency of IgA1. According to comprehensive gene expression analysis, we focused on integrin β1. Pre-treatment by Mn(2+), which activates integrin by changing its structure, enhanced the binding of IgA1 in cultured mesangial cells. Furthermore, pre-incubation with collagens specifically enhanced binding of IgA1 in the cultured human mesangial cells without activation by Mn(2+). Collagen type IV distributed in the mesangial region of the glomeruli as well as Bowman's capsule and tubular basal membrane in IgAN patients, and the IgA1 with collagen type IV induced proliferative signals on mesangial cells by phosphorylating extracellular signal-regulated kinase more effectively than the IgA1 alone. Immunoprecipitation assay revealed the binding of IgA1 and integrin α1/β1 and α2/β1 heterodimer and down-regulation of integrin α1, α2 and β1 expression in human mesangial cells induced by each specific small interfering RNA diminished the ability to bind IgA1 probe. Integrin α1/β1 and α2/β1 would be a candidate receptor for IgA1.

    DOI: 10.1093/intimm/dxr125

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