Homare Shimohata

Publications (23)61.18 Total impact

• Article: Osteomalacia due to Fanconi's syndrome and renal failure caused by long-term low-dose adefovir dipivoxil.

  Homare Shimohata, Shinsuke Sakai, Yujiro Ogawa, Kouichi Hirayama, Masaki Kobayashi
  Clinical and Experimental Nephrology 12/2012; · 1.37 Impact Factor
• Article: Human Parvovirus B19-Induced Acute Glomerulonephritis: A Case Report.

  Homare Shimohata, Takashi Higuchi, Yujiro Ogawa, Shogo Fujita, Miho Nagai, Masahiro Imaizumi, Hiroshi Maruyama, Kouichi Hirayama, Masaki Kobayashi
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  ABSTRACT: Human parvovirus B19 (HPV B19) infection is well known as a cause of erythema infectiosum in children. Acute glomerulonephritis due to HPVB19 infection is rarely observed in adults. Here, we present the case of a 45-year-old female who showed acute glomerulonephritis induced by HPVB19 infection with various autoantibodies. She had proteinuria (175 mg/g creatinine) and hematuria (20-29 erythrocytes per high-power field) in a urinalysis, and various autoantibodies such as antinuclear antibodies, proteinase-3-antineutrophil cytoplasmic antibodies (PR3-ANCA), antiglomerular basement membrane (GBM) antibodies, and anticardiolipin antibodies in a blood examination. A renal biopsy showed that endocapillary proliferative glomerulonephritis comprised of mononuclear cell infiltration. By using immunofluorescence microscopy, IgG, IgA, IgM, C3, C4, and C1q deposits were detected mainly in glomerular capillaries. Electron-dense deposits were detected in the subendothelial area and mesangial area by using electron microscopy. All symptoms and abnormal laboratory data were self-improved. Our patient's case may provide a clue to the etiology of ANCA-associated vasculitis or lupus nephritis.
  Renal Failure 11/2012; · 0.82 Impact Factor
• Article: A case of focal segmental glomerulosclerosis with myeloid bodies.

  Tomoko Kakita, Homare Shimohata, Shogo Fujita, Yujiro Ogawa, Miho Nagai, Kouichi Hirayama, Hideko Nakamura, Masaki Kobayashi
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  ABSTRACT: The presence of myeloid bodies in electron microscopy is a characteristic finding of Fabry's disease. Here, we present a male patient, whose renal biopsy findings suggested the coexistence of focal segmental glomerulosclerosis and Fabry's disease, because of the presence of segmental hyalinosis and/or sclerosis in glomeruli and myeloid bodies in electron microscopy. But finally, Fabry's disease was excluded as a diagnosis because the α-galactosidase A activity in leukocyte and plasma in this patient was within normal limits. After renal biopsy, although he received medication including steroid therapy, his renal function gradually decreased to end-stage renal failure and hemodialysis was initiated. Until now, he does not exhibit any specific symptoms. In conclusion, our case suggests that occasional myeloid bodies in renal biopsy specimens should be interpreted with caution.
  Renal Failure 04/2012; 34(6):801-3. · 0.82 Impact Factor
• Article: A novel diabetes mellitus mouse model, MAFA-deficient and beta cell-specific MAFK-overexpressing hybrid transgenic mice, developed severe diabetic nephropathy and improved with TCV-116 (candesartan cilexetil) treatment.

  Akiko Fujita, Keigyou Yoh, Homare Shimohata, Naoki Morito, Masami Ojima, Midori Okamura, Satoru Takahashi, Kunihiro Yamagata
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  ABSTRACT: Many models of diabetic nephropathy have been reported. However, it is rare that the characteristic findings of severe human diabetic nephropathy, such as diffuse, nodular, and exudative lesions, are all detected in one model mouse. Previously, we reported that MAFA-deficient and beta cell-specific MAFK-overexpressing hybrid transgenic (Mafa(-/-)Mafk (+)) mice develop diabetes mellitus and, after uninephrectomy, demonstrate these characteristic lesions. In this study, we administered TCV-116 (candesartan cilexetil) to Mafa(-/-)Mafk (+) mice after uninephrectomy and examined whether TCV-116 ameliorated the diabetic nephropathy. We also evaluated the utility of these mice as a model for developing treatments for diabetic nephropathy. We performed uninephrectomy of the Mafa(-/-)Mafk (+) mice at 8 weeks old. We then divided these mice into two groups as follows: 1) an untreated group and 2) a group treated with TCV-116 at 5 µg/g/day from 10 to 20 weeks. TCV-116 treatment did not affect serum glucose levels. However, in the treated group, urinary protein excretion, mesangial matrix expansion, enlargement of the kidney, and glomerular surface area were all improved relative to untreated mice. Oxidative stress is known to be increased in diabetic nephropathy and to be suppressed by TCV-116. The urinary level of 8-OHdG, an oxidative stress marker, at 20 weeks was lower in the TCV-116-treated group than in the untreated group. From these results, we concluded that the Mafa(-/-)Mafk (+) mouse is a useful model to analyze diabetic nephropathy and a useful tool for the development of new drugs to treat diabetic nephropathy.
  Experimental Animals 01/2012; 61(1):49-57. · 0.92 Impact Factor
• Article: Serum TNF-related and weak inducer of apoptosis levels in septic shock patients.

  Miho Nagai, Kouichi Hirayama, Itaru Ebihara, Takashi Higuchi, Masahiro Imaizumi, Hiroshi Maruyama, Yasunori Miyamoto, Tomoko Kakita, Yujiro Ogawa, Shogo Fujita, Homare Shimohata, Masaki Kobayashi
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  ABSTRACT: Capillary permeability is a tightly regulated feature of microcirculation in all organ beds. In sepsis, this feature is fundamentally altered. We have previously reported elevated levels of angiopoietin-2 in patients with septic shock, and have investigated tumor necrosis factor (TNF)-related and weak inducer of apoptosis (TWEAK), which mediates both angiogenesis and inflammation, in those patients. Enzyme-linked immunoassay was used to measure serum TWEAK levels in 20 patients with septic shock, all of whom were treated by direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX), and in 20 non-septic controls. The TWEAK levels were higher in patients with septic shock (192.8 ± 230.5 pg/mL) than in controls (84.1 ± 28.7 pg/mL, P = 0.043). Between 11 survivors and 10 non-survivors, there was no significant difference in the serum TWEAK levels before the DHP-PMX therapy. During DHP-PMX therapy, however, the serum TWEAK levels were significantly increased in non-survivors (142.2 ± 88.1 pg/mL to 399.0 ± 307.1 pg/mL, P = 0.022). There was a significant correlation between the serum TWEAK levels and white blood cell counts (r = 0.393, P < 0.001), platelet counts (r = 0.418, P < 0.001), or serum CRP levels (r = 0.259, P = 0.029), but there was no correlation between the serum TWEAK levels and blood pressure. The serum TWEAK levels were also correlated with the ratio of angiopoietin-2 to -1 (r = 0.464, P < 0.001). TWEAK may be a suitable marker of disease severity and mortality in septic patients, and TWEAK levels may be associated with vascular permeability via angiopoietin balance.
  Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 08/2011; 15(4):342-8. · 1.39 Impact Factor
• Article: Serum ratio of soluble triggering receptor expressed on myeloid cells-1 to creatinine is a useful marker of infectious complications in myeloperoxidase-antineutrophil cytoplasmic antibody-associated renal vasculitis.

  Kouichi Hirayama, Miho Nagai, Itaru Ebihara, Homare Shimohata, Masaki Kobayashi, Akio Koyama
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  ABSTRACT: The contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated. Soluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD). There was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection. The serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis.
  Nephrology Dialysis Transplantation 03/2011; 26(3):868-74. · 3.40 Impact Factor
• Article: Serum levels of BAFF and APRIL in myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis: association with disease activity.

  Miho Nagai, Kouichi Hirayama, Itaru Ebihara, Homare Shimohata, Masaki Kobayashi, Akio Koyama
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  ABSTRACT: A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis. APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA-associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications. Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001). Excessive BAFF production in MPO-ANCA-associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production.
  Nephron Clinical Practice 02/2011; 118(4):c339-45. · 2.04 Impact Factor
• Article: Pleuritis caused by Campylobacter jejuni subspecies jejuni in a patient undergoing long-term hemodialysis.

  Miho Nagai, Kouichi Hirayama, Tsuyoshi Ohishi, Homare Shimohata, Kiyofumi Ohkusu, Masaki Kobayashi
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  ABSTRACT: A 73-year-old female hemodialysis patient experienced fever, shortness of breath on effort, and chest discomfort. A decrease in breath sounds in the right lung field, leukocytosis, elevated CRP level, and a right massive pleural effusion were observed. The patient was diagnosed with bacterial pleuritis based on leukocyte-predominant exudative pleural effusion, and treated with ceftriaxone. Her symptoms, however, were not improved, so thoracic drainage was attempted. Campylobacter species were isolated from cultured pleural fluid samples, and Campylobacter jejuni subspecies jejuni was detected on the multiplex PCR assay. The antibiotic was therefore changed to minocycline following pazufloxacin, and her symptoms were improved.
  Internal Medicine 01/2010; 49(22):2481-6. · 0.94 Impact Factor
• Article: Mizoribine reduces serum KL-6 levels in ANCA-associated vasculitis.

  Shogo Fujita, Kouichi Hirayama, Yujiro Ogawa, Homare Shimohata, Masaki Kobayashi
  Clinical and Experimental Nephrology 12/2009; 14(2):203-4. · 1.37 Impact Factor
• Article: Angiopoietin balance in septic shock patients treated by direct hemoperfusion with polymyxin b-immobilized fiber.

  Itaru Ebihara, Kouichi Hirayama, Kei Nagai, Tomoko Kakita, Yasunori Miyamoto, Miho Nagai, Yujiro Ogawa, Shogo Fujita, Homare Shimohata, Hirayasu Kai, Joichi Usui, Kunihiro Yamagata, Masaki Kobayashi
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  ABSTRACT: Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. We previously reported elevated levels of vascular endothelial growth factor and its receptor (fms-like tyrosine kinase-1) in patients with septic shock, then investigated two kinds of angiopoietins in those patients. An enzyme-linked immunoassay was used to measure serum angiopoietin-1 and -2 levels in 12 patients with septic shock who were treated by direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX). The angiopoietin-1 level was lower in patients with septic shock (7.01 +/- 10.08 ng/mL) than in controls (28.24 +/- 11.61 ng/mL, P < 0.001), but the angiopoietin-2 level was higher in septic shock patients (40.83 +/- 30.13 ng/mL vs. 2.47 +/- 1.78 ng/mL, P < 0.001). Between seven survivors and five non-survivors there was no significant difference in angiopoietin-1 levels before DHP-PMX therapy. During DHP-PMX therapy, however, the angiopoietin-2 level was significantly decreased in survivors (31.52 +/- 26.15 ng/mL vs. 17.32 +/- 22.46 ng/mL, P = 0.035). Moreover, at the end of the therapy, the angiopoietin-1 level was significantly lower in non-survivors (1.14 +/- 1.30 ng/mL vs. 10.43 +/- 13.56 ng/mL, P = 0.042), but the angiopoietin-2 level in non-survivors was significantly higher (70.79 +/- 40.47 ng/mL vs. 17.32 +/- 22.46 ng/mL, P = 0.019). The angiopoietin-2 level may be associated with vascular permeability in septic patients, and angiopoietins may be suitable markers of disease severity and mortality.
  Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 12/2009; 13(6):520-7. · 1.39 Impact Factor
• Article: Analysis of T-cell receptor usage in myeloperoxidase--antineutrophil cytoplasmic antibody-associated renal vasculitis.

  Kouichi Hirayama, Takashi Ishizu, Homare Shimohata, Yasunori Miyamoto, Tomoko Kakita, Miho Nagai, Yujiro Ogawa, Shogo Fujita, Aki Hirayama, Kunihiro Yamagata, Masaki Kobayashi, Akio Koyama
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  ABSTRACT: Bacterial superantigens produced by Staphylococcus aureus may be associated with the onset of proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, including Wegener's granulomatosis. We investigated T-cell subsets to assess the superantigens present in patients with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis. Peripheral-blood mononuclear cells (PBMC) obtained from 40 normal controls and ten patients with MPO-ANCA-associated vasculitis were stained with fluorescence-labeled monoclonal antibodies against T-cell markers, including 17 variable regions of T-cell receptor beta-chains (TCR-Vbeta) and were then analyzed using flow cytometry. Among PBMCs, the percentage of CD3(+) cells from patients with MPO-ANCA-associated vasculitis was significantly lower than that from normal controls, but there were no differences between the two groups in the percentage of CD19(+) cells or CD16(+) cells. Although there were no differences regarding the overall percentage of CD4(+) cells between the two groups, the percentage of CD4(+)CD45RO(+) cells in patients with MPO-ANCA-associated vasculitis was significantly higher than that in normal controls, and percentages of CD4(+)CD45RO(+)HLA-DR(+) and CD4(+)CD45RO(+)CD62L(low) cells in patients with MPO-ANCA-associated vasculitis were also significantly increased. There was no significant difference between the two groups in terms of the usage of the 17 different TCR-Vbeta regions. There was no difference in bacterial superantigens between controls and MPO-ANCA-associated vasculitis patients because of the absence of specific usage of TCR-Vbeta regions. Given the elevated levels of memory T cells, conventional antigens rather than superantigens may be associated with the pathogenesis of MPO-ANCA-associated vasculitis.
  Clinical and Experimental Nephrology 10/2009; 14(1):36-42. · 1.37 Impact Factor
• Article: MafA-deficient and beta cell-specific MafK-overexpressing hybrid transgenic mice develop human-like severe diabetic nephropathy.

  Homare Shimohata, Keigyou Yoh, Akiko Fujita, Naoki Morito, Masami Ojima, Hiromi Tanaka, Kouichi Hirayama, Masaki Kobayashi, Takashi Kudo, Kunihiro Yamagata, Satoru Takahashi
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  ABSTRACT: Transcription factor MafA is a key molecule in insulin secretion and the development of pancreatic islets. Previously, we demonstrated that some of the MafA-deficient mice develop overt diabetes mellitus, and the phenotype of these mice seems to be mild probably because of redundant functions of other Maf proteins. In this study, we generated hybrid transgenic mice that were MafA-deficient and also over-expressed MafK specifically in beta cells (MafA(-/-)MafK(+)). MafA(-/-)MafK(+) mice developed severe overt diabetes mellitus within 5weeks old, and showed higher levels of proteinuria and serum creatinine. Histological analysis revealed that embryonic development of beta cells in the MafA(-/-)MafK(+) mice was significantly suppressed and the reduced number of beta cells was responsible for the early onset of diabetes. Furthermore, after uninephrectomy, these mice demonstrated three characteristics of human diabetic nephropathy: diffuse, nodular, and exudative lesions. MafA(-/-)MafK(+) mice might be a useful model for the analysis of human diabetic nephropathy.
  Biochemical and Biophysical Research Communications 09/2009; 389(2):235-40. · 2.48 Impact Factor
• Article: Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice.

  Keigyou Yoh, Aki Hirayama, Kazusa Ishizaki, Akiko Yamada, Masayoshi Takeuchi, Sho-ichi Yamagishi, Naoki Morito, Takako Nakano, Masami Ojima, Homare Shimohata, Ken Itoh, Satoru Takahashi, Masayuki Yamamoto
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  ABSTRACT: The transcription factor Nrf2 regulates the expression of antioxidant genes. Hyperglycemia-induced oxidative stress is involved in the pathogenesis of diabetes and its complications. However, little is known about the protective role of Nrf2 in diabetes. To gain insight into the protective role of Nrf2 in diabetes we treated Nrf2 knockout (Nrf2 KO) mice with streptozotocin (STZ). The STZ Nrf2 KO mice did not develop renal hyperfiltration, which was observed in the STZ-treated wild-type (STZ WT) mice, but renal function gradually deteriorated over the 10-week observation period. Urinary excretion of nitric oxide metabolites and the occurrence of 8-nitroguanosine, which was detected in glomerular lesions, were increased in STZ Nrf2 KO mice during the early stages after treatment. In vivo electron paramagnetic resonance analysis revealed an accelerated rate of decay of the 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl spin probe signal in STZ Nrf2 KO mice. The addition of superoxide dismutase prolonged the half-life of the signal, which suggested that increased oxygen radical formation occurred in the STZ Nrf2 KO mice. These results suggested that hyperglycemia increased oxidative and nitrosative stress and accelerated renal injury in the Nrf2 KO mice and that Nrf2 serves as a defense factor against some diabetic complications.
  Genes to Cells 12/2008; 13(11):1159-70. · 2.68 Impact Factor
• Article: Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2‐deficient mice

  Keigyou Yoh, Aki Hirayama, Kazusa Ishizaki, Akiko Yamada, Masayoshi Takeuchi, Sho-ichi Yamagishi, Naoki Morito, Takako Nakano, Masami Ojima, Homare Shimohata, Ken Itoh, Satoru Takahashi, Masayuki Yamamoto
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  ABSTRACT: The transcription factor Nrf2 regulates the expression of antioxidant genes. Hyperglycemia-induced oxidative stress is involved in the pathogenesis of diabetes and its complications. However, little is known about the protective role of Nrf2 in diabetes. To gain insight into the protective role of Nrf2 in diabetes we treated Nrf2 knockout (Nrf2 KO) mice with streptozotocin (STZ). The STZ Nrf2 KO mice did not develop renal hyperfiltration, which was observed in the STZ-treated wild-type (STZ WT) mice, but renal function gradually deteriorated over the 10-week observation period. Urinary excretion of nitric oxide metabolites and the occurrence of 8-nitroguanosine, which was detected in glomerular lesions, were increased in STZ Nrf2 KO mice during the early stages after treatment. In vivo electron paramagnetic resonance analysis revealed an accelerated rate of decay of the 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl spin probe signal in STZ Nrf2 KO mice. The addition of superoxide dismutase prolonged the half-life of the signal, which suggested that increased oxygen radical formation occurred in the STZ Nrf2 KO mice. These results suggested that hyperglycemia increased oxidative and nitrosative stress and accelerated renal injury in the Nrf2 KO mice and that Nrf2 serves as a defense factor against some diabetic complications.
  Genes to Cells 10/2008; 13(11):1159 - 1170. · 2.68 Impact Factor
• Article: Nitric oxide protection against adriamycin-induced tubulointerstitial injury.

  Takaaki Oteki, Sohji Nagase, Homare Shimohata, Aki Hirayama, Atsushi Ueda, Hidekatsu Yokoyama, Tetsuhiko Yoshimura
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  ABSTRACT: It is well known that oxidative stress is related to the pathogenesis of adriamycin (ADR) nephropathy. However, it is unclear how nitric oxide (NO) is associated with the pathophysiological process after ADR administration. The NO level in a kidney homogenate was assayed by electron paramagnetic resonance (EPR) spectrometry using a direct in vivo NO trapping technique after ADR administration. N-(3-(aminomethyl)benzyl)acetamidine (1400W) was used as a specific, inducible nitric oxide synthase (iNOS) inhibitor. The levels of NO after ADR administration gradually increased for 6 h and then decreased until 24 h after ADR administration. The fractional excretion of Na (FE(Na)) in the urine was elevated in the ADR group on day 1. Pre-treatment of the animals with 1400W attenuated the increase in NO levels despite further elevation of FE(Na). These findings suggest that iNOS-derived NO does not produce a harmful effect but rather protects the ADR-treated kidney against sodium excretion.
  Free Radical Research 03/2008; 42(2):154-61. · 2.88 Impact Factor
• Article: Th1 and type 1 cytotoxic T cells dominate responses in T-bet overexpression transgenic mice that develop contact dermatitis.

  Kazusa Ishizaki, Akiko Yamada, Keigyou Yoh, Takako Nakano, Homare Shimohata, Atsuko Maeda, Yuki Fujioka, Naoki Morito, Yasuhiro Kawachi, Kazuko Shibuya, Fujio Otsuka, Akira Shibuya, Satoru Takahashi
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  ABSTRACT: Contact dermatitis in humans and contact hypersensitivity (CHS) in animal models are delayed-type hypersensitivity reactions mediated by hapten-specific T cells. Recently, it has become clear that both CD4(+) Th1 and CD8(+) type 1 cytotoxic T (Tc1) cells can act as effectors in CHS reactions. T-bet has been demonstrated to play an important role in Th1 and Tc1 cell differentiation, but little is known about its contribution to CHS. In the present study, we used C57BL/6 mice transgenic (Tg) for T-bet to address this issue. These Tg mice, which overexpressed T-bet in their T lymphocytes, developed dermatitis characterized by swollen, flaky, and scaly skin in regions without body hair. Skin histology showed epidermal hyperkeratosis, neutrophil, and lymphocyte infiltration similar to that seen in contact dermatitis. T-bet overexpression in Tg mice led to elevated Th1 Ig (IgG2a) and decreased Th2 Ig (IgG1) production. Intracellular cytokine analyses demonstrated that IFN-gamma was increased in both Th1 and Tc1 cells. Furthermore, Tg mice had hypersensitive responses to 2,4-dinitrofluorobenzene, which is used for CHS induction. These results suggest that the level of expression of T-bet might play an important role in the development of contact dermatitis and that these Tg mice should be a useful model for contact dermatitis.
  The Journal of Immunology 02/2007; 178(1):605-12. · 5.79 Impact Factor
• Article: MafK overexpression in pancreatic beta-cells caused impairment of glucose-stimulated insulin secretion.

  Homare Shimohata, Keigyou Yoh, Naoki Morito, Hitoshi Shimano, Takashi Kudo, Satoru Takahashi
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  ABSTRACT: MafA is a member of large Maf transcription factors and activates the insulin gene in pancreatic beta-cells. Other large Maf transcription factors, MafB and c-Maf, also express and activate insulin transcription in beta-cells. However, the functional relationship between MafA and other Maf proteins in beta-cells has not been established. In order to suppress the function of large Maf proteins, we generated transgenic mice overexpressing MafK, which act as dominant negative protein in pancreatic beta-cells. These mice showed hyperglycemia at a young age due to impairment of glucose-stimulated insulin secretion. Although the transgenic mice showed an abnormal response in the glucose tolerance test, hyperglycemia was restored in adulthood. Histological analysis revealed islet hypertrophy in adult transgenic mice. Finally, an electrophoretic gel mobility shift assay showed that the DNA-binding activity of endogenous MafA was significantly increased in the MafK transgenic mice. These results indicated that MafA may have relevance to compensatory response.
  Biochemical and Biophysical Research Communications 09/2006; 346(3):671-80. · 2.48 Impact Factor
• Article: Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human.

  Naoki Morito, Keigyou Yoh, Yuki Fujioka, Takako Nakano, Homare Shimohata, Yuko Hashimoto, Akiko Yamada, Atsuko Maeda, Fumihiko Matsuno, Hiroyuki Hata, Atsushi Suzuki, Shigehiko Imagawa, Hiroaki Mitsuya, Hiroyasu Esumi, Akio Koyama, Masayuki Yamamoto, Naoyoshi Mori, Satoru Takahashi
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  ABSTRACT: c-Maf translocation or overexpression has been observed in human multiple myeloma. Although c-maf might function as an oncogene in multiple myeloma, a role for this gene in other cancers has not been shown. In this study, we have found that mice transgenic for c-Maf whose expression was direct to the T-cell compartment developed T-cell lymphoma. Moreover, we showed that cyclin D2, integrin beta(7), and ARK5 were up-regulated in c-Maf transgenic lymphoma cells. Furthermore, 60% of human T-cell lymphomas (11 of 18 cases), classified as angioimmunoblastic T-cell lymphoma, were found to express c-Maf. These results suggest that c-Maf might cause a type of T-cell lymphoma in both mice and humans and that ARK5, in addition to cyclin D2 and integrin beta(7), might be downstream target genes of c-Maf leading to malignant transformation.
  Cancer Research 02/2006; 66(2):812-9. · 7.86 Impact Factor
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  Available from: ncbi.nlm.nih.gov

  Article: MafA is a key regulator of glucose-stimulated insulin secretion.

  Chuan Zhang, Takashi Moriguchi, Miwako Kajihara, Ritsuko Esaki, Ayako Harada, Homare Shimohata, Hisashi Oishi, Michito Hamada, Naoki Morito, Kazuteru Hasegawa, Takashi Kudo, James Douglas Engel, Masayuki Yamamoto, Satoru Takahashi
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  ABSTRACT: MafA is a transcription factor that binds to the promoter in the insulin gene and has been postulated to regulate insulin transcription in response to serum glucose levels, but there is no current in vivo evidence to support this hypothesis. To analyze the role of MafA in insulin transcription and glucose homeostasis in vivo, we generated MafA-deficient mice. Here we report that MafA mutant mice display intolerance to glucose and develop diabetes mellitus. Detailed analyses revealed that glucose-, arginine-, or KCl-stimulated insulin secretion from pancreatic beta cells is severely impaired, although insulin content per se is not significantly affected. MafA-deficient mice also display age-dependent pancreatic islet abnormalities. Further analysis revealed that insulin 1, insulin 2, Pdx1, Beta2, and Glut-2 transcripts are diminished in MafA-deficient mice. These results show that MafA is a key regulator of glucose-stimulated insulin secretion in vivo.
  Molecular and Cellular Biology 07/2005; 25(12):4969-76. · 5.53 Impact Factor
• Article: Transgenic overexpression of GATA-3 in T lymphocytes improves autoimmune glomerulonephritis in mice with a BXSB/MpJ-Yaa genetic background.

  Keigyou Yoh, Kazuko Shibuya, Naoki Morito, Takako Nakano, Kazusa Ishizaki, Homare Shimohata, Masato Nose, Shozo Izui, Akira Shibuya, Akio Koyama, James Douglas Engel, Masayuki Yamamoto, Satoru Takahashi
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  ABSTRACT: A T helper 1 (Th1)/Th2 imbalance is thought to contribute to the pathogenesis of autoimmune diseases. The differentiation of T cells into Th1 or Th2 subtypes is under the regulation of several transcription factors. Among these, transcription factor GATA-3 is thought to play an indispensable role in the development of T cells and the differentiation of Th2 cells. To examine how a Th1/Th2 imbalance affects the development of autoimmune disease, GATA-3 was overexpressed in the T lymphocytes of C57BL/6 x BXSB/MpJ-Yaa F(1) (Yaa) mice. Yaa mice developed autoimmune nephritis similarly to BXSB/MpJ-Yaa mice, which are commonly used as a model for Th1-dominant murine lupus. GATA-3 overexpression in T cells improved the 50% mortality incidence time for GATA-3-transgenic Yaa mice (41.6 wk), compared with Yaa mice (30.9 wk), and reduced proteinuria, serum creatinine levels, and the severity of glomerulonephritis in GATA-3-transgenic Yaa mice. GATA-3 overexpression in Yaa mice led to simultaneously elevated Th2 Ig (IgG1) and decreased Th1 Ig (IgG2a and IgG3) production and serum IFN-gamma levels. Although IL-4 production remained unchanged, intracellular cytokine analyses demonstrated that IL-5 was induced and IFN-gamma was suppressed in stimulated T cells from the GATA-3-transgenic Yaa mice. These results indicated that abundant GATA-3 was unable to stimulate complete differentiation of Th2 cells but did counteract the dominance of Th1 cells and alleviated the disease severity in Yaa mice. These data suggest that transcriptional regulation therapy may have potential as an effective strategy for treating autoimmune glomerulonephritis.
  Journal of the American Society of Nephrology 11/2003; 14(10):2494-502. · 9.66 Impact Factor