2021/07/09 更新

写真a

キタムラ シンジ
喜多村 真治
KITAMURA Shinji
所属
岡山大学病院 講師
職名
講師
外部リンク

学位

  • 医学博士 ( 2004年3月   岡山大学 )

所属学協会

 

論文

  • Feasible kidney donation with living marginal donors, including diabetes mellitus. 国際誌

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Takanori Sekito, Shogo Watari, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Kohei Edamura, Yasuyuki Kobayashi, Katsuyuki Tanabe, Hidemi Takeuchi, Masashi Kitagawa, Shinji Kitamura, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Immunity, inflammation and disease   2021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)  

    OBJECTIVES: To compare the donor outcomes of living donor kidney transplantation between standard donors (SDs) and marginal donors (MDs) including diabetic patients (MD + DM). METHODS: MDs were defined according to Japanese guideline criteria: (a) age >70-years, (b) blood pressure ≤130/80 mmHg on hypertension medicine, (c) body mass index >25 to ≤32 kg/m2 , (d) 24-h creatinine clearance ≥70 to <80 ml/min/1.73 m2 , and (e) hemoglobin A1c > 6.2 or ≤6.5 with oral diabetic medicine. Fifty-three of 114 donors were MDs. We compared donor kidney functions until 60 months postoperatively. RESULTS: No kidney function parameters were different between SDs and MDs. When comparing SD and MD + DM, MD + DM had a lower postoperative eGFR (48 vs. 41 (1 (month), p = .02), 49 vs. 40 (12, p < .01), 48 vs. 42 (24, p = .04), 47 vs. 38 (36, p = .01)) and the percentage of residual eGFR (SD vs. MD + DM: 63 vs. 57 (1 (month), p < .01), 63 vs. 57 (2, p < .01), 64 vs. 56 (12, p < .01), 63 vs. 57 (24, p < .01), 63 vs. 52 (36, p = .02)). However, when MD with a single risk factor of DM was compared to SD, the difference disappeared. Nine out of 12 (75%) MD + DM had ≥2 risk factors. CONCLUSIONS: Although long-term observation of donor kidney function is necessary, careful MD + DM selection had the potential to expand the donor pool.

    DOI: 10.1002/iid3.470

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  • ABO Blood Incompatibility Positively Affects Early Graft Function: Single-Center Retrospective Cohort Study. 国際誌

    Shogo Watari, Motoo Araki, Koichiro Wada, Kasumi Yoshinaga, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Transplantation proceedings   53 ( 5 )   1494 - 1500   2021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)  

    BACKGROUND: We investigated the association between ABO-incompatible (ABO-I) kidney transplantation and early graft function. METHODS: We retrospectively analyzed 95 patients who underwent living donor kidney transplantation between May 2009 and July 2019. It included 61 ABO-compatible (ABO-C) and 34 ABO-I transplantations. We extracted data on immunologic profile, sex, age, cold ischemic time, type of immunosuppression, and graft function. Two definitions were used for slow graft function (SGF) as follows: postoperative day (POD) 3 serum creatinine level >3 mg/dL and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2. Logistic regression analysis was performed to analyze the effect of ABO-I on the incidence of SGF. RESULTS: The characteristics between the ABO-C and ABO-I were not different. ABO-I received rituximab and plasma exchange. Patients also received tacrolimus and mycophenolate mofetil for 2 weeks and prednisolone for 1 week before transplantation as preconditioning. Of the 95 study patients, 19 (20%) and 21 (22%) were identified with SGF according to POD 3 serum creatinine level or eGFR, respectively. Multivariable analysis revealed that ABO-I significantly reduced the incidence of SGF (odds ratio, 0.15; 95% confidence interval, 0.03-0.7; P = .02), and cold ischemic time >150 min increased the incidence of SGF (odds ratio, 6.5; 95% confidence interval, 1.7-25; P = .006). Similar results were identified in POD 3 eGFR. Inferior graft function in patients with SGF was identified up to 6 months after transplantation. CONCLUSION: ABO-I reduces the incidence of SGF, which is associated with an inferior graft function up to 6 months.

    DOI: 10.1016/j.transproceed.2021.03.043

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  • MicroRNAs as Biomarkers for Nephrotic Syndrome. 国際誌

    Kenji Tsuji, Shinji Kitamura, Jun Wada

    International journal of molecular sciences   22 ( 1 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.

    DOI: 10.3390/ijms22010088

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  • Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection. 国際誌

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Haruhito Adam Uchida, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   27 ( 12 )   1136 - 1142   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. METHODS: A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. RESULTS: There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups. CONCLUSIONS: Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.

    DOI: 10.1111/iju.14382

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  • Tubulointerstitial Nephritis Cases With IgM-Positive Plasma Cells. 国際誌

    Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Kazuhiko Fukushima, Shinji Kitamura, Haruhito A Uchida, Hitoshi Sugiyama, Naoki Takahashi, Masayuki Iwano, Jun Wada

    Kidney international reports   5 ( 9 )   1576 - 1580   2020年9月

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  • Podocytopathy as 'stand-alone' involvement in systemic lupus erythematosus: a case report. 国際誌

    Kenji Tsuji, Yoko Takatsu, Yu Katayama, Kazuhiko Fukushima, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada

    Lupus   29 ( 9 )   1148 - 1150   2020年8月

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  • Tubulointerstitial Nephritis and Uveitis Caused by Sjögren Syndrome Without Dryness. 国際誌

    Soichiro Sugitani, Kenji Tsuji, Toshio Yamanari, Yoichi Hasegawa, Kentaro Inoue, Yuka Sogabe, Yukari Nakano, Shinji Kitamura, Tsutomu Ishizu, Jun Wada

    Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases   2020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)  

    DOI: 10.1097/RHU.0000000000001505

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  • Deep Learning Could Diagnose Diabetic Nephropathy with Renal Pathological Immunofluorescent Images. 国際誌

    Shinji Kitamura, Kensaku Takahashi, Yizhen Sang, Kazuhiko Fukushima, Kenji Tsuji, Jun Wada

    Diagnostics (Basel, Switzerland)   10 ( 7 )   2020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)  

    Artificial Intelligence (AI) imaging diagnosis is developing, making enormous steps forward in medical fields. Regarding diabetic nephropathy (DN), medical doctors diagnose them with clinical course, clinical laboratory data and renal pathology, mainly evaluate with light microscopy images rather than immunofluorescent images because there are no characteristic findings in immunofluorescent images for DN diagnosis. Here, we examined the possibility of whether AI could diagnose DN from immunofluorescent images. We collected renal immunofluorescent images from 885 renal biopsy patients in our hospital, and we created a dataset that contains six types of immunofluorescent images of IgG, IgA, IgM, C3, C1q and Fibrinogen for each patient. Using the dataset, 39 programs worked without errors (Area under the curve (AUC): 0.93). Five programs diagnosed DN completely with immunofluorescent images (AUC: 1.00). By analyzing with Local interpretable model-agnostic explanations (Lime), the AI focused on the peripheral lesion of DN glomeruli. On the other hand, the nephrologist diagnostic ratio (AUC: 0.75833) was slightly inferior to AI diagnosis. These findings suggest that DN could be diagnosed only by immunofluorescent images by deep learning. AI could diagnose DN and identify classified unknown parts with the immunofluorescent images that nephrologists usually do not use for DN diagnosis.

    DOI: 10.3390/diagnostics10070466

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  • Adult kidney stem/progenitor cells contribute to regeneration through the secretion of trophic factors. 国際誌

    Kenji Tsuji, Shinji Kitamura, Yizhen Sang, Kazuhiko Fukushima, Jun Wada

    Stem cell research   46   101865 - 101865   2020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)  

    Adult kidney stem cells are known to have important roles in renal regeneration after acute kidney injury. Although trophic factors from tissue stem cells have been reported to promote the regeneration of other organs, there is limited number of evidence of this phenomenon in the kidneys. Here, we explored the effects of secreted factors from kidney stem cells. We intraperitoneally administered culture supernatant obtained from adult rat kidney stem/progenitor cells into rat kidney ischemia/reperfusion injury models, and the treatment significantly ameliorated renal tubulointerstitial injury, suppressed tubular cell apoptosis, diminished inflammation and promoted the proliferation of both residual renal cells and immature cells. In vitro, treatment with culture supernatant from kidney stem cells significantly promoted cell proliferation and suppressed cisplatin-induced cell apoptosis in both normal rat kidney cells and kidney stem cells. In addition, treatment with culture supernatant increased the expression of nestin in normal rat kidney cells, suggesting the dedifferentiation of tubular cells into stem-like cells. Analysis of the culture supernatant revealed that it contained a variety of growth factors. Taken together, the results suggest that these factors together lead to renal regeneration. In conclusion, adult kidney stem cells contribute to renal regeneration indirectly through the secretion of regenerative factors.

    DOI: 10.1016/j.scr.2020.101865

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  • Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury. 国際誌

    Yizhen Sang, Kenji Tsuji, Akiko Inoue-Torii, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada

    International journal of molecular sciences   21 ( 11 )   2020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)  

    Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.

    DOI: 10.3390/ijms21114099

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  • Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice. 国際誌

    Kazuhiko Fukushima, Shinji Kitamura, Kenji Tsuji, Yizhen Sang, Jun Wada

    International journal of molecular sciences   21 ( 11 )   2020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)  

    Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i-HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

    DOI: 10.3390/ijms21114054

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  • Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report. 国際誌

    Natsumi Matsuoka, Kenji Tsuji, Eiki Ichihara, Takayuki Hara, Kazuhiko Fukushima, Kishio Toma, Shinji Kitamura, Kenichi Inagaki, Hitoshi Sugiyama, Jun Wada

    BMC nephrology   21 ( 1 )   113 - 113   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. CASE PRESENTATION: A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. CONCLUSION: All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed.

    DOI: 10.1186/s12882-020-01775-z

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  • Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases. 国際誌

    Kenji Tsuji, Shinji Kitamura, Jun Wada

    International journal of molecular sciences   21 ( 3 )   2020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)  

    Mesenchymal stem cells (MSCs) have immunomodulatory and regenerative effects in many organs, including the kidney. Emerging evidence has shown that the trophic effects from MSCs are mainly mediated by the paracrine mechanism rather than the direct differentiation of MSCs into injured tissues. These secretomes from MSCs include cytokines, growth factors, chemokines and extracellular vesicles (EVs) containing microRNAs, mRNAs, and proteins. Many research studies have revealed that secretomes from MSCs have potential to ameliorate renal injury in renal disease models, including acute kidney injury and chronic kidney disease through a variety of mechanisms. These trophic mechanisms include immunomodulatory and regenerative effects. In addition, accumulating evidence has uncovered the specific factors and therapeutic mechanisms in MSC-derived EVs. In this article, we summarize the recent advances of immunomodulatory and regenerative effects of EVs from MSCs, especially focusing on the microRNAs.

    DOI: 10.3390/ijms21030756

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  • Identification of Proteins Differentially Expressed by Adipose-derived Mesenchymal Stem Cells Isolated from Immunodeficient Mice. 国際誌

    Yoshiki Nakashima, Saifun Nahar, Chika Miyagi-Shiohira, Takao Kinjo, Naoya Kobayashi, Shinji Kitamura, Issei Saitoh, Masami Watanabe, Jiro Fujita, Hirofumi Noguchi

    International journal of molecular sciences   20 ( 11 )   2019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)  

    Although cell therapy using adipose-derived mesenchymal stem cells (AdMSCs) regulates immunity, the degree to which cell quality and function are affected by differences in immunodeficiency of donors is unknown. We used liquid chromatography tandem-mass spectrometry (LC MS/MS) to identify the proteins expressed by mouse AdMSCs (mAsMSCs) isolated from normal (C57BL/6) mice and mice with severe combined immunodeficiency (SCID). The protein expression profiles of each strain were 98%-100% identical, indicating that the expression levels of major proteins potentially associated with the therapeutic effects of mAdMSCs were highly similar. Further, comparable levels of cell surface markers (CD44, CD90.2) were detected using flow cytometry or LC MS/MS. MYH9, ACTN1, CANX, GPI, TPM1, EPRS, ITGB1, ANXA3, CNN2, MAPK1, PSME2, CTPS1, OTUB1, PSMB6, HMGB1, RPS19, SEC61A1, CTNNB1, GLO1, RPL22, PSMA2, SYNCRIP, PRDX3, SAMHD1, TCAF2, MAPK3, RPS24, and MYO1E, which are associated with immunity, were expressed at higher levels by the SCID mAdMSCs compared with the C57BL/6 mAdMSCs. In contrast, ANXA9, PCBP2, LGALS3, PPP1R14B, and PSMA6, which are also associated with immunity, were more highly expressed by C57BL/6 mAdMSCs than SCID mAdMSCs. These findings implicate these two sets of proteins in the pathogenesis and maintenance of immunodeficiency.

    DOI: 10.3390/ijms20112672

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  • A Novel Preservation Solution Containing a JNK Inhibitory Peptide Efficiently Improves Islet Yield for Porcine Islet Isolation. 国際誌

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Nana Ebi, Eri Hamada, Yoshihito Tamaki, Kazuho Kuwae, Shinji Kitamura, Naoya Kobayashi, Issei Saitoh, Masami Watanabe

    Transplantation   103 ( 2 )   344 - 352   2019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: For islet transplantation, pancreas preservation in University of Wisconsin (UW) solution is associated with disadvantages, such as collagenase inhibition, resulting in poor islet yield and islets with poor viability. In this study, we evaluated a novel preservation solution, the extracellular-type c-Jun N-terminal kinase (JNK) inhibitor-containing (EJ) solution. METHODS: The EJ solution has high sodium-low potassium composition with low viscosity compared to UW solution. Moreover, EJ solution contains a recently developed JNK inhibitor from our laboratory. RESULTS: We first compared the performance of EJ solution with that of UW solution. Islet yield before and after purification was significantly higher in the EJ group than in the UW group. Second, we compared the performance of EJ solution with that of EJ solution without the JNK inhibitor (EJ-J solution). After pancreas preservation in EJ solution, JNK activity was maintained at a relatively low level during islet isolation. Islet yield before and after purification was significantly higher in the EJ group than in the EJ-J group. After islet transplantation into streptozotocin-induced diabetic mice, blood glucose levels reached the normoglycemic range in 61.5% and 7.7% of diabetic mice in the EJ and EJ-J groups, respectively. Moreover, EJ solution exhibited reduced inhibition of collagenase digestion compared with UW solution. CONCLUSIONS: Advantages of EJ solution over UW solution were inhibition of JNK activity and reduced collagenase inhibition. EJ solution may therefore be more suitable for islet isolation than UW solution.

    DOI: 10.1097/TP.0000000000002555

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  • Induction of Expandable Adipose-Derived Mesenchymal Stem Cells from Aged Mesenchymal Stem Cells by a Synthetic Self-Replicating RNA. 国際誌

    Chika Miyagi-Shiohira, Yoshiki Nakashima, Naoya Kobayashi, Shinji Kitamura, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    International journal of molecular sciences   19 ( 11 )   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adipose-derived mesenchymal stem cells (ADSCs) have attracted attention due to their potential for use in the treatment of various diseases. However, the self-renewal capacity of ADSCs is restricted and their function diminishes during passage. We previously generated induced tissue-specific stem cells from mouse pancreatic cells using a single synthetic self-replicating Venezuelan Equine Encephalitis (VEE)-reprogramming factor (RF) RNA replicon (SR-RNA) expressing the reprogramming factors POU class 5 homeobox 1 (OCT4), Krueppel-like factor 4 (KLF4), Sex determining region Y-box 2 (SOX2), and Glis Family Zinc Finger 1 (GLIS1). This vector was used to generate induced pluripotent stem (iPS) cells. Here, we applied this SR-RNA vector to generate human iTS cells from aged mesenchymal stem cells (hiTS-M cells) deficient in self-renewal that were derived from adipose tissue. These hiTS-M cells transfected with the SR-RNA vector survived for 15 passages. The hiTS-M cells expressed cell surface markers similar to those of human adipose-derived mesenchymal stem cells (hADSCs) and differentiated into fat cells and osteoblasts. Global gene expression profiling showed that hiTS-M cells were transcriptionally similar to hADSCs. These data suggest that the generation of iTS cells has important implications for the clinical application of autologous stem cell transplantation.

    DOI: 10.3390/ijms19113489

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  • Secretomes from Mesenchymal Stem Cells against Acute Kidney Injury: Possible Heterogeneity. 国際誌

    Kenji Tsuji, Shinji Kitamura, Jun Wada

    Stem cells international   2018   8693137 - 8693137   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A kidney has the ability to regenerate itself after a variety of renal injuries. Mesenchymal stem cells (MSCs) have been shown to ameliorate tissue damages during renal injuries and diseases. The regenerations induced by MSCs are primarily mediated by the paracrine release of soluble factors and extracellular vesicles, including exosomes and microvesicles. Extracellular vesicles contain proteins, microRNAs, and mRNAs that are transferred into recipient cells to induce several repair signaling pathways. Over the past few decades, many studies identified trophic factors from MSCs, which attenuate renal injury in a variety of animal acute kidney injury models, including renal ischemia-reperfusion injury and drug-induced renal injury, using microarray and proteomic analysis. Nevertheless, these studies have revealed the heterogeneity of trophic factors from MSCs that depend on the cell origins and different stimuli including hypoxia, inflammatory stimuli, and aging. In this review article, we summarize the secretomes and regenerative mechanisms induced by MSCs and highlight the possible heterogeneity of trophic factors from different types of MSC and different circumstances for renal regeneration.

    DOI: 10.1155/2018/8693137

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  • The level of urinary semaphorin3A is associated with disease activity in patients with minimal change nephrotic syndrome. 国際誌

    Akiko Inoue-Torii, Shinji Kitamura, Jun Wada, Kenji Tsuji, Hirofumi Makino

    International journal of nephrology and renovascular disease   10   167 - 174   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Semaphorin3A is a secreted protein known to be involved in organogenesis, immune responses and cancer. In the kidney, semaphorin3A is expressed in the glomerular podocytes, distal tubules and collecting tubules, and believed to play a role in the regulation of the kidney development and function. We examined the serum and urinary semaphorin3A levels in 72 patients with renal disease and 5 healthy volunteers. The patients had been diagnosed with thin basement membrane disease (n=4), minimal change nephrotic syndrome (MCNS; n=22), IgA nephritis (n=21), membranous nephropathy (n=16) and focal segmental glomerular sclerosis (n=9). The level of urinary semaphorin3A in MCNS patients tended to be relatively high among all disease groups. We also investigated the urinary semaphorin3A level in 7 patients with MCNS from disease onset to remission during the drug therapy. MCNS patients in pre-remission states had higher urinary semaphorin3A levels than those in post-remission states receiving immunosuppressive therapies. These results suggested that the urinary semaphorin3A level correlates with the MCNS activity. Semaphorin3A has the potential as a biomarker for MCNS to clarify the reactivity for therapy and may be useful in examining other glomerular diseases with proteinuria as well.

    DOI: 10.2147/IJNRD.S132980

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  • Single adult kidney stem/progenitor cells reconstitute three-dimensional nephron structures in vitro. 国際誌

    Shinji Kitamura, Hiroyuki Sakurai, Hirofumi Makino

    Stem cells (Dayton, Ohio)   33 ( 3 )   774 - 84   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The kidneys are formed during development from two distinct primordial tissues, the metanephric mesenchyme and the ureteric bud. The metanephric mesenchyme develops into the kidney nephron, the minimal functional unit of the kidney. A nephron consists of several segments and regulates water, electrolyte, and acid-base homeostasis in addition to secreting certain hormones. It has been predicted that the kidney will be among the last organs successfully regenerated in vitro due to its complex structure and multiple functions. Here, we show that adult kidney stem/progenitor cells (KS cells), derived from the S3 segment of adult rat kidney nephrons, can reconstitute a three-dimensional kidney-like structure in vitro. Kidney-like structures were formed when a cluster of KS cells was suspended in an extracellular matrix gel and cultured in the presence of several growth factors. Morphological analyses revealed that these kidney-like structures contained every substructure of the kidney, including glomeruli, proximal tubules, the loop of Henle, distal tubules, and collecting ducts, but no vasculature. Our results demonstrate that a cluster of tissue stem/progenitor cells has the ability to reconstitute the minimum unit of its organ of origin by differentiating into specialized cells in the correct location. This process differs from embryonic kidney development, which requires the mutual induction of two different populations of progenitors, metanephric mesenchymal cells and ureteric bud cells.

    DOI: 10.1002/stem.1891

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  • Autoimmune pancreatitis and minimal change nephrotic syndrome: an unusual association? 国際誌

    Yuka Okuyama, Haruhito Adam Uchida, Masafumi Tenta, Tomokazu Nunoue, Ryoko Umebayashi, Hiroshi Morinaga, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Jun Wada

    Nephrology (Carlton, Vic.)   20 ( 3 )   225 - 6   2015年3月

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    記述言語:英語  

    DOI: 10.1111/nep.12370

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  • Trophic Factors from Tissue Stem Cells for Renal Regeneration. 国際誌

    Kenji Tsuji, Shinji Kitamura

    Stem cells international   2015   537204 - 537204   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stem cell therapies against renal injury have been advancing. The many trials for renal regeneration are reported to be effective in many kinds of renal injury models. Regarding the therapeutic mechanism, it is believed that stem cells contribute to make regeneration via not only direct stem cell differentiation in the injured space but also indirect effect via secreted factors from stem cells. Direct differentiation from stem cells to renal composed cells has been reported. They differentiate to renal composed cells and make functions. However, regarding renal regeneration, stem cells are discussed to secrete many kinds of growth factors, cytokines, and chemokines in paracrine or autocrine manner, which protect against renal injury, too. In addition, it is reported that stem cells have the ability to communicate with nearby cells via microvesicle-related RNA and proteins. Taken together from many reports, many secreted factors from stem cells were needed for renal regeneration orchestrally with harmony. In this review, we focused on the effects and insights of stem cells and regenerative factors from stem cells.

    DOI: 10.1155/2015/537204

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  • Hypoxia-inducible factor 1α regulates branching morphogenesis during kidney development. 国際誌

    Kenji Tsuji, Shinji Kitamura, Hirofumi Makino

    Biochemical and biophysical research communications   447 ( 1 )   108 - 14   2014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)  

    The kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13Ks) and cultured the organs under normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. E13Ks cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-α1), increased under hypoxic conditions in E13Ks. When we cultured E13Ks with the HIF-1α inhibitor digoxin or with siRNA targeting HIF-1α under hypoxic conditions, we did not observe increased UB branching. In addition, the expression of GDNF and GFR-α1 was inhibited under hypoxic conditions when the kidneys were treated with siRNA targeting HIF-1α. We also elucidated that hypoxia inhibited UB cell apoptosis and promoted the expression of FGF7 mRNA levels in metanephric mesenchymal (MM) cells in vitro. These findings suggest that hypoxic condition has important roles in inducing branching morphogenesis during kidney development. Hypoxia might mediate branching morphogenesis via not only GDNF/Ret but also FGF signaling pathway.

    DOI: 10.1016/j.bbrc.2014.03.111

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  • The selection of peritoneal mesothelial cells is important for cell therapy to prevent peritoneal fibrosis. 国際誌

    Shinji Kitamura, Naoya Horimoto, Kenji Tsuji, Akiko Inoue, Keiichi Takiue, Hitoshi Sugiyama, Hirofumi Makino

    Tissue engineering. Part A   20 ( 3-4 )   529 - 39   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)  

    Long-term peritoneal dialysis (PD) causes chronic peritoneal damage. Peritoneal mesothelial cells (PMCs) play an important role in peritoneal function. We investigated the possibility of cell therapy using the PMCs to prevent peritoneal damage in PD patients. We harvested human PMCs from the PD effluent of PD patients. The PMCs were separated based on morphological characteristics into epithelial-like (Epi) cells and fibroblast-like (Fib) cells by the limiting dilution method. We transplanted these cells into nude mice whose parietal and visceral peritoneum were scratched by mechanical scraping. The transplanted cells were detected at the parietal and visceral peritoneum. Compared with the positive control, the Epi cell therapy group showed very few adhesions and exhibited no thickening of the parietal and visceral peritoneum. However, the group with Fib cell therapy could not inhibit peritoneal adhesion and thickening. In addition, hepatocyte growth factor was expressed by the grafted Epi cells but not Fib cells. Fib cells expressed vascular endothelial growth factor stronger than Epi cells. These two types of cells from the same patient showed different characteristics and effects for cell therapy. These findings suggest that the PMCs from the PD patient showed different characteristics, such as Epi cells and Fib cells, and the selection of PMCs is important for cell therapy on the point of not only the direct cellular interactions but also cytokine secretion from the grafted cells. Furthermore, the differences in the morphological cell characteristics may influence their role in peritoneal regeneration.

    DOI: 10.1089/ten.TEA.2013.0130

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  • Mizoribine inhibits the proliferation of renal stem/progenitor cells by G1/S arrest during renal regeneration.

    Naoya Horimoto, Shinji Kitamura, Kenji Tsuji, Hirofumi Makino

    Acta medica Okayama   68 ( 1 )   7 - 15   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immunosuppressive agents are generally administered to treat kidney diseases. However, it is unclear whether renal stem/progenitor cells are directly affected by the immunosuppressive agents. We used normal rat kidney cells, ureteric bud cells and rat kidney stem/progenitor cells in this study. Mizoribine (MZR), cyclophosphamide (CPA) and cyclosporine (CyA) were added to the culture media of these cells. We evaluated the effects of these immunosuppressive agents on cell proliferation using an electrical cell-substrate impedance sensing system (ECIS) and their effects on the process of renal regeneration using the ischemia-reperfusion (I/R) injury rat model. The ECIS data showed that proliferation of each of the 3 types of cells was significantly suppressed by MZR. MZR treatment enhanced renal tubular injury in ischemia-reperfusion (I/R) injured rats, and significantly decreased levels of M-phase cells and Nestin-positive cells. These results suggested that MZR inhibits the cell cycle of renal stem/progenitor cells;thus, physicians should take note that MZR might affect not only inflammation but also renal regeneration.

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  • Membranous nephropathy with acquired factor V inhibitor: a case report. 国際誌

    Shinji Kitamura, Mahito Misawa, Sayaka Namba, Kenji Tsuji, Rikako Torigoe, Midori Shima, Hirofumi Makino

    BMC research notes   6   553 - 553   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. In contrast, acquired factor V inhibitor is a rare bleeding disorder. CASE PRESENTATION: A 62-year-old Asian man with a history of cerebral hemorrhage, purpura, eosinophilia and hyper immunoglobulin E syndrome developed proteinuria. The bleeding disorder was diagnosed with acquired factor V inhibitors. A renal biopsy revealed that he suffered from membranous nephropathy with glomerular endothelial damage which is reported to be involved in another factor disorder. After the steroid administration, the coagulation test and proteinuria were improved. CONCLUSIONS: The presence of factor V inhibitors may have been involved in the development of membranous nephropathy.

    DOI: 10.1186/1756-0500-6-553

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  • A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. 国際誌

    Masashi Kitagawa, Hitoshi Sugiyama, Hiroshi Morinaga, Tatsuyuki Inoue, Keiichi Takiue, Ayu Ogawa, Toshio Yamanari, Yoko Kikumoto, Haruhito Adam Uchida, Shinji Kitamura, Yohei Maeshima, Kazufumi Nakamura, Hiroshi Ito, Hirofumi Makino

    PloS one   8 ( 2 )   e56695   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD). METHODS: We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification. RESULTS: The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075). CONCLUSIONS: Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.

    DOI: 10.1371/journal.pone.0056695

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  • Right hypoplastic kidney. 国際誌

    Ayu Ogawa, Shinji Kitamura, Kazunori Nakayama, Hitoshi Sugiyama, Naoya Morisada, Kazumoto Iijima, Hirofumi Makino

    Kidney international   82 ( 9 )   1037 - 1037   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/ki.2012.201

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  • A case of focal segmental glomerulosclerosis in an adult patient with hypogammaglobulinemia superimposed on membranoproliferative glomerulonephritis in childhood. 国際誌

    Kenji Tsuji, Haruhito Adam Uchida, Tetsuichirou Ono, Tatsuyuki Inoue, Katsuji Shinagawa, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Hirofumi Makino

    BMC nephrology   13   46 - 46   2012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)  

    BACKGROUND: Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia without a known predisposing cause. CASE PRESENTATION: We report a 36-year-old man who had suffered membranoproliferative glomerulonephritis (MPGN) in his childhood, later diagnosed with CVID at 35 years of age. He presented at our hospital with signs of proteinuria. A renal biopsy revealed he suffered from focal segmental glomerulosclerosis (FSGS), possibly due to obesity and hypertension, not CVID - associated MPGN. CONCLUSION: This is the first case report of FSGS in a CVID patient. In this case, we have to pay attention not only to the treatment of obesity and hypertension for FSGS but also to the recurrence of immune-complex glomerulonephritis such as MPGN, in case of the restoration of hypogammaglobulinemia.

    DOI: 10.1186/1471-2369-13-46

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  • Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis. 国際誌

    Keiichi Takiue, Hitoshi Sugiyama, Tatsuyuki Inoue, Hiroshi Morinaga, Yoko Kikumoto, Masashi Kitagawa, Shinji Kitamura, Yohei Maeshima, Da-Hong Wang, Noriyoshi Masuoka, Keiki Ogino, Hirofumi Makino

    BMC nephrology   13   14 - 14   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model. METHODS: ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups. RESULTS: The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation. CONCLUSIONS: These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.

    DOI: 10.1186/1471-2369-13-14

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  • Suppression of adiponectin by aberrantly glycosylated IgA1 in glomerular mesangial cells in vitro and in vivo. 国際誌

    Tatsuyuki Inoue, Hitoshi Sugiyama, Masashi Kitagawa, Keiichi Takiue, Hiroshi Morinaga, Ayu Ogawa, Yoko Kikumoto, Shinji Kitamura, Yohei Maeshima, Hirofumi Makino

    PloS one   7 ( 3 )   e33965   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The pathogenesis of IgA nephropathy (IgAN) may be associated with the mesangial deposition of aberrantly glycosylated IgA1. To identify mediators affected by aberrantly glycosylated IgA1 in cultured human mesangial cells (HMCs), we generated enzymatically modified desialylated and degalactosylated (deSial/deGal) IgA1. The state of deglycosylated IgA1 was confirmed by lectin binding to Helix aspersa (HAA) and Sambucus nigra (SNA). In the cytokine array analysis, 52 proteins were upregulated and 34 were downregulated in HMCs after stimulation with deSial/deGal IgA1. Among them, the secretion of adiponectin was suppressed in HMCs after stimulation with deSial/deGal IgA1. HMCs expressed mRNAs for adiponectin and its type 1 receptor, but not the type 2 receptor. Moreover, we revealed a downregulation of adiponectin expression in the glomeruli of renal biopsy specimens from patients with IgAN compared to those with lupus nephritis. We also demonstrated that aberrantly glycosylated IgA1 was deposited in the mesangium of patients with IgAN by dual staining of HAA and IgA. Moreover, the urinary HAA/SNA ratio of lectin binding was significantly higher in IgAN compared to other kidney diseases. Since adiponectin has anti-inflammatory effects, including the inhibition of adhesion molecules and cytokines, these data suggest that the local suppression of this adipokine by aberrantly glycosylated IgA1 could be involved in the regulation of glomerular inflammation and sclerosis in IgAN.

    DOI: 10.1371/journal.pone.0033965

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  • Serum high-sensitivity cardiac troponin T is a significant biomarker of left-ventricular diastolic dysfunction in subjects with non-diabetic chronic kidney disease. 国際誌

    Masashi Kitagawa, Hitoshi Sugiyama, Hiroshi Morinaga, Tatsuyuki Inoue, Keiichi Takiue, Yoko Kikumoto, Haruhito Adam Uchida, Shinji Kitamura, Yohei Maeshima, Norihisa Toh, Kazufumi Nakamura, Hiroshi Ito, Hirofumi Makino

    Nephron extra   1 ( 1 )   166 - 77   2011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: Chronic kidney disease (CKD) is associated with left-ventricular (LV) diastolic dysfunction (LVDD) which progresses to diastolic heart failure. However, biomarkers predicting LVDD in patients with CKD are largely unknown. METHODS: In 93 patients with non-diabetic CKD, the relationships among echocardiography, high-sensitivity cardiac troponin T (hs-cTnT), B-type natriuretic peptide (BNP), and renal function were evaluated. LV mass index, peak early diastolic mitral filling velocity (E), peak early diastolic mitral annular velocity (E'), and E/E' were recorded. RESULTS: The E' values were significantly decreased and E/E', BNP, and hs-cTnT increased with increasing CKD stage. The CKD patients with LVDD with E' <5 cm/s had a significantly higher hs-cTnT level as well as a significantly higher BNP level compared to those with E' ≥5 cm/s. The area under the receiver-operating characteristic curve for hs-cTnT and BNP to detect E' <5 cm/s was 0.880 (p = 0.0101) and 0.741 (p = 0.0570), respectively. In multivariate analysis, hs-cTnT and albuminuria were significantly associated with E', and estimated glomerular filtration rate with the hs-cTnT level, after adjusting for age, cause of CKD, and other parameters. CONCLUSIONS: These data suggest that hs-cTnT may be a useful biomarker of LVDD in non- diabetic CKD patients.

    DOI: 10.1159/000333801

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  • High glucose increases metallothionein expression in renal proximal tubular epithelial cells. 国際誌

    Daisuke Ogawa, Masato Asanuma, Ikuko Miyazaki, Hiromi Tachibana, Jun Wada, Norio Sogawa, Takeshi Sugaya, Shinji Kitamura, Yohei Maeshima, Kenichi Shikata, Hirofumi Makino

    Experimental diabetes research   2011   534872 - 534872   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Metallothionein (MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

    DOI: 10.1155/2011/534872

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  • Neuropeptide Y functions as a facilitator of GDNF-induced budding of the Wolffian duct. 国際誌

    Yohan Choi, James B Tee, Thomas F Gallegos, Mita M Shah, Hideto Oishi, Hiroyuki Sakurai, Shinji Kitamura, Wei Wu, Kevin T Bush, Sanjay K Nigam

    Development (Cambridge, England)   136 ( 24 )   4213 - 24   2009年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ureteric bud (UB) emergence from the Wolffian duct (WD), the initiating step in metanephric kidney morphogenesis, is dependent on GDNF; however, GDNF by itself is generally insufficient to induce robust budding of the isolated WD in culture. Thus, additional factors, presumably peptides or polypeptide growth factors, might be involved. Microarray data from in vivo budding and non-budding conditions were analyzed using non-negative matrix factorization followed by gene ontology filtering and network analysis to identify sets of genes that are highly regulated during budding. These included the GDNF co-receptors GFRalpha1 and RET, as well as neuropeptide Y (NPY). By using ANOVA with pattern matching, NPY was also found to correlate most significantly to the budded condition with a high degree of connectedness to genes with developmental roles. Exogenous NPY [as well as its homolog, peptide YY (PYY)] augmented GDNF-dependent budding in the isolated WD culture; conversely, inhibition of NPY signaling or perturbation of NPY expression inhibited budding, confirming that NPY facilitates this process. NPY was also found to reverse the decreased budding, the downregulation of RET expression, the mislocalization of GFRalpha1, and the inhibition of AKT phosphorylation that resulted from the addition of BMP4 to the isolated WD cultures, suggesting that NPY acts through the budding pathway and is reciprocally regulated by GDNF and BMP4. Thus, the outgrowth of the UB from the WD might result from a combination of the upregulation of the GDNF receptors together with genes that support GDNF signaling in a feed-forward loop and/or counteraction of the inhibitory pathway regulated by BMP4.

    DOI: 10.1242/dev.037580

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  • Beta1-integrin is required for kidney collecting duct morphogenesis and maintenance of renal function. 国際誌

    Wei Wu, Shinji Kitamura, David M Truong, Timo Rieg, Volker Vallon, Hiroyuki Sakurai, Kevin T Bush, David R Vera, Robert S Ross, Sanjay K Nigam

    American journal of physiology. Renal physiology   297 ( 1 )   F210-7   2009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)  

    Deletion of integrin-beta1 (Itgb1) in the kidney collecting system led to progressive renal dysfunction and polyuria. The defect in the concentrating ability of the kidney was concomitant with decreased medullary collecting duct expression of aquaporin-2 and arginine vasopressin receptor 2, while histological examination revealed hypoplastic renal medullary collecting ducts characterized by increased apoptosis, ectasia and cyst formation. In addition, a range of defects from small kidneys with cysts and dilated tubules to bilateral renal agenesis was observed. This was likely due to altered growth and branching morphogenesis of the ureteric bud (the progenitor tissue of the renal collecting system), despite the apparent ability of the ureteric bud-derived cells to induce differentiation of the metanephric mesenchyme. These data not only support a role for Itgb1 in the development of the renal collecting system but also raise the possibility that Itgb1 links morphogenesis to terminal differentiation and ultimately collecting duct function and/or maintenance.

    DOI: 10.1152/ajprenal.90260.2008

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  • Unique microstructures and podocytic infolding in glomerular basement membrane associated with collagen diseases: a report of three cases.

    Hitoshi Sugiyama, Mie Maruyama, Hiroshi Morinaga, Tatsuyuki Inoue, Kei-Ichi Takiue, Yoko Kikumoto, Masaru Kinomura, Ken-Ei Sada, Shigeru Akagi, Shinji Kitamura, Yohei Maeshima, Hirofumi Makino

    Clinical and experimental nephrology   12 ( 6 )   450 - 4   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Unique renal histopathological appearances, consisting of podocytic infolding and microstructures in the glomerular basement membrane (GBM) were identified in the renal biopsies from three patients with collagen diseases such as systemic lupus erythematosus (lupus nephritis, class II) and Sjögren's syndrome. In each case, the GBM contained microstructures, including microspheres and microtubular structures, accompanied by podocytic infolding into the GBM when examined by electron microscope. The size of the microstructures in the GBM ranged from 40 to 160 nm. Glomerular endothelial cells also seemed to be infolded in the GBM in a case with lupus nephritis. The response to glucocorticoid therapy was favorable in two cases. The cause of these morphological changes in the GBM might be associated with autoimmune disorders.

    DOI: 10.1007/s10157-008-0098-6

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  • Amelioration of cisplatin-induced acute renal injury by renal progenitor-like cells derived from the adult rat kidney. 国際誌

    Masaru Kinomura, Shinji Kitamura, Katsuyuki Tanabe, Kunihiro Ichinose, Kumiko Hirokoshi, Yuki Takazawa, Hiroyuki Kitayama, Tatsuyo Nasu, Hitoshi Sugiyama, Yasushi Yamasaki, Takeshi Sugaya, Yohei Maeshima, Hirofumi Makino

    Cell transplantation   17 ( 1-2 )   143 - 58   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The replacement of a necrotic tubular epithelium with functional tubular epithelial cells is required for recovery from acute renal failure (ARF). A rat renal progenitor-like (rKS56) cell line was recently established derived from the S3 segment of renal proximal tubules. The therapeutic efficacy of rKS56 cells was examined in a rat model of cisplatin-induced ARF. rKS56-lacZ cells expressing 3-galactosidase were injected into SD rats either at the subcapsule of the left kidney (rKS-SC) or via the left renal artery (rKS-IA) 2 days after the injection of cisplatin. Bluo-gal(+) rKS56-lacZ cells were observed in the subcapsule in the rKS-SC group on day 5, and were further increased in number on day 9, accompanied by partial distribution in the corticomedullary junction, but not in the rKS-IA group. A portion of Bluo-gal(+) cells coexpressed Ki-67, aquaporin-1, hepatocyte growth factor (HGF), and c-Met. rKS-SC treatment significantly improved the tubular injury scores, ameliorated tubular cell apoptosis, and induced cell proliferation. The renal function also significantly improved in the rKS-SC group on day 5. These results demonstrate that locally implanted rKS56 cells could differentiate into tubular epithelial cells, thereby accelerating the recovery from tubular injury, most likely by producing tubular trophic factors. These results suggest the therapeutic potential of this novel approach for patients with end-stage renal failure.

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  • Glial cell-derived neurotrophic factor independent ureteric bud outgrowth from the Wolffian duct. 国際誌

    Akito Maeshima, Hiroyuki Sakurai, Yohan Choi, Shinji Kitamura, Duke A Vaughn, James B Tee, Sanjay K Nigam

    Journal of the American Society of Nephrology : JASN   18 ( 12 )   3147 - 55   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • [Regenerative system of injured renal tubules].

    Shinji Kitamura, Yohei Maeshima, Hirofumi Makino

    Nihon rinsho. Japanese journal of clinical medicine   64 Suppl 2   58 - 61   2006年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Establishment and characterization of renal progenitor like cells from S3 segment of nephron in rat adult kidney. 国際誌

    Shinji Kitamura, Yasushi Yamasaki, Masaru Kinomura, Takeshi Sugaya, Hitoshi Sugiyama, Yohei Maeshima, Hirofumi Makino

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   19 ( 13 )   1789 - 97   2005年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Kidney is thought to be a regenerative organ in terms of repair from acute tubular injury. It is unknown whether cell population contributes to repair disordered kidney. We attempted to identify and isolate highly proliferative cells from a single cell. We dissected a single nephron from adult rat kidney. Isolated nephrons were separated into segments and cultured. Outgrowing cells were replated after limiting dilution so that each well contained a single cell. One of cell line which was the most potent to grow was designated as rKS56. rKS56 cells showed cobblestone appearance and expressed immature cell markers relating to kidney development and mature tubular cell markers. rKS56 cells grew exponentially and could be maintained for 300 days without transformation. In different culture conditions, rKS56 cells differentiated into mature tubular cells defined by aquaporin-1, 2 expression, and responsiveness to parathyroid hormone or vasopressin. Engrafted to kidney in rat ischemic reperfusion model, rKS56 cells replaced in injured tubules in part after implantation and improved renal function. These results suggest rKS56 cells possess character such as self-renewal, multi-plasticity and capability of tissue repair. rKS56 may possibly contribute to the future development of cell therapy for renal regeneration.

    PubMed

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  • Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. 国際誌

    Yoshihiko Yamamoto, Yohei Maeshima, Hiroyuki Kitayama, Shinji Kitamura, Yuki Takazawa, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino

    Diabetes   53 ( 7 )   1831 - 40   2004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)  

    In the early stage of diabetic nephropathy (one of the major microvascular complications of diabetes) glomerular hyperfiltration and hypertrophy are observed. It is clinically important to regulate glomerular hypertrophy for preventing glomerulosclerosis. The number of glomerular endothelial cells is known to be increased in diabetic nephropathy associated with enlarged glomerular tufts, suggesting that the mechanism is similar to that of angiogenesis. Tumstatin peptide is an angiogenesis inhibitor derived from type IV collagen and inhibits in vivo neovascularization induced by vascular endothelial growth factor (VEGF), one of the mediators of glomerular hypertrophy in diabetic nephropathy. Here, we show the effect of tumstatin peptide in inhibiting alterations in early diabetic nephropathy. Glomerular hypertrophy, hyperfiltration, and albuminuria were suppressed by tumstatin peptide (1 mg/kg) in streptozotocin-induced diabetic mice. Glomerular matrix expansion, the increase of total glomerular cell number and glomerular endothelial cells (CD31 positive), and monocyte/macrophage accumulation was inhibited by tumstatin peptide. Increase in renal expression of VEGF, flk-1, and angiopoietin-2, an antagonist of angiopoietin-1, was inhibited by tumstatin treatment in diabetic mice. Alteration of glomerular nephrin expression, a podocyte protein crucial for maintaining glomerular filtration barrier, was recovered by tumstatin in diabetic mice. Taken together, these results demonstrate the potential use of antiangiogenic tumstatin peptide as a novel therapeutic agent in early diabetic nephropathy.

    PubMed

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  • Transforming growth factor-beta 1 induces vascular endothelial growth factor expression in murine proximal tubular epithelial cells. 国際誌

    Shinji Kitamura, Yohei Maeshima, Takeshi Sugaya, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino

    Nephron. Experimental nephrology   95 ( 2 )   e79-86   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that promotes angiogenesis, vasculogenesis, and increases vascular permeability. VEGF is expressed in renal tubular epithelial cells and urinary VEGF excretion is increased in various glomerular disorders. However, the mechanisms underlying expression of VEGF in renal tubular epithelial cells have not been fully elucidated. In the present study, we attempted to define a predominant regulator of VEGF expression using a cultured murine renal proximal tubular epithelial cell line (mProx24). VEGF protein concentration in the culture supernatant was measured by sandwich enzyme-linked immunosorbent assay. mProx24 constitutively produced VEGF at low level. Major isoforms expressed in this cell line were VEGF164 and VEGF120 determined by reverse transcription-polymerase chain reaction method. Among various stimuli including angiotensin II, transforming growth factor-beta1 (TGF-beta1), lipopolysaccharides, interleukin-1beta, interleukin-10 and interferon-gamma, only TGF-beta1 significantly increased the level of VEGF protein at 24 h in a dose-dependent manner. The steady-state mRNA level of VEGF was dose dependently increased by TGF-beta1 detected by Northern blotting. Treatment with neutralizing anti-TGF-beta1 antibody abolished TGF-beta1-induced VEGF expression by 70%. Inhibitors of protein kinase C (PKC), Ro-31-8220 and staurosporin, significantly suppressed TGF-beta1-induced VEGF protein expression. These results demonstrate the role of TGF-beta1 on the expression of VEGF in proximal tubular epithelial cells mediated potentially via PKC pathway. This regulatory mechanism may be associated with the progression of tubulointerstitial lesions in renal disorders.

    PubMed

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共同研究・競争的資金等の研究

  • Semaphorin3aによる糸球体上皮細胞の機能的障害機序の解明

    研究課題/領域番号:18K08244  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    喜多村 真治

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    慢性腎臓病は日本国民の約8人に一人が罹患する国民病でもある。そのような腎臓病の進展因子は蛋白尿が主であり、その腎臓病への新たな治療ストラテジーとして、semaphorin3aを介した腎機能重症化抑制を目指した病態機序の解明を行った。我々は臨床研究において、糸球体細胞形態的障害が少ない微小変化型ネフ ローゼ症候群とsemaphorin3aとの関係について報告した。今回の研究では、基礎的に糸球体上皮細胞障害とsemaphorin3aとの病態機序解明から新たな治療法の開 発を行った。昨年度は主に糸球体障害、特に上皮細胞障害を継続して解析を行った。In Vivo実験として、糸球体上皮細胞モデルとしてアドリアマイシン誘発腎症モデルを作製し、糸球体障害を惹起し、それらに対し、semaphorinの関連を解析した。また、semaphorin阻害剤を投与した群も作製し、semaphorin阻害による糸球体上皮細胞 保護効果も確認した。この研究からsemaphorin阻害剤による抗蛋白尿効果が認められた。また、In Vitro実験では、培養糸球体上皮細胞を用いて、In Vivoと同様にアドリアマイシン刺激による上皮細胞障害を作製し、 semaphorin阻害剤による保護効果も確認した。これらは、c-JUN経路に関与することが示唆された。現在、研究を論文化して投稿中である。

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  • 腹膜透析における腹膜中皮細胞動態からみた腹膜硬化進展機序の解明

    研究課題/領域番号:26461252  2014年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    喜多村 真治, 辻 憲二, 鳥居 章子

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    In Vitro試験では形態的、質的評価を行った。用いた細胞は腹膜中皮細胞で敷石状形態細胞(以下Epi細胞)及び線維芽様腹膜中皮細胞(以下Fib細胞)で行った。酸性刺激のみならず、糖刺激においてもEpi細胞の変化は乏しいが、Fib細胞が腹膜硬化に重要な働きを行うことが示唆された。次にIn Vivo試験ではEpi細胞上清では腹膜硬化モデルに比較し、有意に腹膜肥厚並びに腹膜癒着を改善したが、Fib細胞上清では反対に有意に腹膜肥厚並びに腹膜癒着の悪化が認められた。このことから、腹膜中皮細胞は分泌する液性因子も重要であることが示唆された。今後液性因子内のエクソソーム解析も行い、機序解明を目指したい。

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  • 成体腎臓幹前駆細胞からの腎臓様構造物と胎生腎を使用した発生・再生的機能解析

    研究課題/領域番号:23700537  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    喜多村 真治

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    我々は、成体腎臓から得られた腎臓幹/前駆細胞を使用して三次元培養することにより腎臓の最小構成単位であるネフロン構造を試験管内で作成することに成功したが、遺伝子学的にも胎生腎臓との比較検討をすることにより、再生研究の基礎的な検討を行うものである。成体腎臓幹/前駆細胞から腎臓構造再構築と発生腎である胎生13日腎、胎生17日腎、成体腎との遺伝子発現についてDNAアレイにて解析を行った。遺伝子学的に発生腎とほぼ同じ程度の一致率が見いだされ、顕微鏡レベルの構築のみならず、遺伝子発現などにおいても発生と同様の遺伝子発現と近似していることが確認された。しかし、形態構築過程との相違もあり、更なる検討が必要と考える。

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