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| 1.
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Nasti, Alessandro ; Sakai, Yoshio ; Seki, Akihiro ; Buffa, Geraldine Belen ; Komura, Takuya ; Mochida, Hatsune ; Yamato, Masatoshi ; Yoshida, Keiko ; Ho, Tuyen T. B. ; Takamura, Masayuki ; Usui, Soichiro ; Wada, Takashi ; Honda, Masao ; Kaneko, Shuichi ; 酒井, 佳夫 ; 餅田, 初音 ; 吉田, 佳子 ; 高村, 雅之 ; 薄井, 荘一郎 ; 和田, 隆志 ; 本多, 政夫 ; 金子, 周一
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金沢大学医薬保健研究域医学系<br />Stromal cells in adipose tissue are useful for repair/regenerative therapy as they harbor a substant
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ial number of mesenchymal stem cells; therefore, freshly isolated autologous uncultured adipose tissue derived stromal cells (u-ADSCs) are useful for regenerative therapy, and obviate the need for mesenchymal stem cells. We evaluated the therapeutic effect of murine u-ADSCs and sorted subsets of u-ADSCs in a concanavalin A (ConA) induced murine model of hepatitis, as well as their characteristics. We found that 10–20% of u-ADSCs expressed the CD45 leukocyte-related antigen. CD68, which is a marker of macrophages (MΦs), was expressed by 50% of CD45+ u-ADSCs. About 90% of CD68+CD45+ cells expressed CD206 antigen, which is a marker of inhibitory M2-type MΦs. Genes related to M2-type MUs were especially more highly expressed by CD45+CD206+ u-ADSCs than by CD45− u-ADSCs. CD45+ u-ADSCs inhibited the expression of cytokines/chemokines and suppressed the proliferation of splenocytes stimulated with ConA. We observed that not only whole u-ADSCs, but also the CD45+ subset of u-ADSCs ameliorated the ConA-induced hepatitis in mice. In conclusion, we show that freshly isolated murine u-ADSCs were effective against acute hepatitis, and CD45+ u-ADSCs acting phenotypically and functionally like M2-type MΦs, contributed to the repair of liver tissue undergoing inflammation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim<br />Embargo Period 12 months
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| 2.
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Yamanouchi, Masayuki ; Hoshino, Junichi ; Ubara, Yoshifumi ; Takaichi, Kenmei ; Kinowaki, Keiichi ; Fujii, Takeshi ; Ohashi, Kenichi ; Mise, Koki ; Toyama, Tadashi ; Hara, Akinori ; Kitagawa, Kiyoki ; Shimizu, Miho ; Furuichi, Kengo ; Wada, Takashi ; 原, 章規 ; 古市, 賢吾 ; 清水, 美保 ; 和田, 隆志
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金沢大学医薬保健研究域医学系<br />Background There have been a limited number of biopsy-based studies on diabetic nephropathy, and the
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refore the clinical importance of renal biopsy in patients with diabetes in late-stage chronic kidney disease (CKD) is still debated. We aimed to clarify the renal prognostic value of pathological information to clinical information in patients with diabetes and advanced CKD. Methods We retrospectively assessed 493 type 2 diabetics with biopsy-proven diabetic nephropathy in four centers in Japan. 296 patients with stage 3–5 CKD at the time of biopsy were identified and assigned two risk prediction scores for end-stage renal disease (ESRD): the Kidney Failure Risk Equation (KFRE, a score composed of clinical parameters) and the Diabetic Nephropathy Score (D-score, a score integrated pathological parameters of the Diabetic Nephropathy Classification by the Renal Pathology Society (RPS DN Classification)). They were randomized 2:1 to development and validation cohort. Hazard Ratios (HR) of incident ESRD were reported with 95% confidence interval (CI) of the KFRE, D-score and KFRE+D-score in Cox regression model. Improvement of risk prediction with the addition of D-score to the KFRE was assessed using c-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results During median follow-up of 1.9 years, 194 patients developed ESRD. The cox regression analysis showed that the KFRE,D-score and KFRE+D-score were significant predictors of ESRD both in the development cohort and in the validation cohort. The c-statistics of the D-score was 0.67. The c-statistics of the KFRE was good, but its predictive value was weaker than that in the miscellaneous CKD cohort originally reported (c-statistics, 0.78 vs. 0.90) and was not significantly improved by adding the D-score (0.78 vs. 0.79, p = 0.83). Only continuous NRI was positive after adding the D-score to the KFRE (0.4%; CI: 0.0–0.8%). Conclusions We found that the predict values of the KFRE and the D-score were not as good as reported, and combining the D-score with the KFRE did not significantly improve prediction of the risk of ESRD in advanced diabetic nephropathy. To improve prediction of renal prognosis for advanced diabetic nephropathy may require different approaches with combining clinical and pathological parameters that were not measured in the KFRE and the RPS DN Classification. © 2018 Yamanouchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Wada, Takashi ; Hosoya, Tatsuo ; Honda, Daisuke ; Sakamoto, Ryusuke ; Narita, Kazutaka ; Sasaki, Tomomitsu ; Okui, Daisuke ; Kimura, Kenjiro ; 和田, 隆志
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金沢大学医薬保健研究域医学系<br />Background: Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in dia
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betic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study. Methods: The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level. Results: At 28 weeks, there was no significant difference in the percent change from baseline in the urinary albumin-to-creatinine ratio between the two groups (topiroxostat: 0 vs. placebo: 17%, p = 0.3206), but the changes in the estimated glomerular filtration rate (− 0.2 vs. − 4.0 mL/min/1.73 m2, p = 0.0303) and the serum uric acid level (− 2.94 vs. − 0.20 mg/dL, p < 0.0001) were significantly different between the topiroxostat and placebo groups. Gouty arthritis occurred in 1 patient in the placebo group and no patients in the topiroxostat group. Conclusion: These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients. © 2018 The Author(s)<br />Embargo Period 12 months
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Furuichi, Kengo ; Yuzawa, Yukio ; Shimizu, Miho ; Hara, Akinori ; Toyama, Tadashi ; Kitamura, Hiroshi ; Suzuki, Yoshiki ; Sato, Hiroshi ; Uesugi, Noriko ; Ubara, Yoshifumi ; Hisano, Satoshi ; Ueda, Yoshihiko ; Nishi, Shinichi ; Yokoyama, Hitoshi ; Nishino, Tomoya ; Kohagura, Kentaro ; Ogawa, Daisuke ; Mise, Koki ; Shibagaki, Yugo ; Kimura, Kenjiro ; Haneda, Masakazu ; Makino, Hirofumi ; Matsuo, Seiichi ; Wada, Takashi ; 古市, 賢吾 ; 清水, 美保 ; 原, 章規 ; 遠山, 直志 ; 和田, 隆志
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金沢大学医薬保健研究域医学系<br />Background. The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are div
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erse, but large-scale pathologic studies with long-termobservations are limited. Methods. Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results. During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions. This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients. © The Author 2017.<br />Embargo Period 12 months
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Hara, Akinori ; Furuichi, Kengo ; Koshino, Akihiko ; Yasuda, Haruka ; Tran, Trang Thi Thu ; Iwata, Yasunori ; Sakai, Norihiko ; Shimizu, Miho ; Kaneko, Shuichi ; Nakamura, Hiroyuki ; Wada, Takashi ; 原, 章規 ; 古市, 賢吾 ; 岩田, 恭宜 ; 坂井, 宣彦 ; 清水, 美保 ; 金子, 周一 ; 中村, 裕之 ; 和田, 隆志
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金沢大学医薬保健研究域医学系<br />Introduction: We examined the impact of autoantibodies on the erythropoietin receptor (EPOR) in type
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2 diabetic patients with chronic kidney disease (CKD). Methods: A total of 112 Japanese patients with type 2 diabetes who had CKD were enrolled in this study and followed for a mean of 45 months. Sera from these patients were screened for anti-EPOR antibodies using enzyme-linked immunosorbent assays. Results: Anti-EPOR antibodies were detected in 26 patients (23%). Anti-EPOR antibodies were associated with low hemoglobin concentrations and decreased renal function. In patients with biopsy-proven diabetic nephropathy, anti-EPOR antibodies were associated with increased levels of interstitial inflammation. A decrease in renal function was observed more frequently in patients with antibodies than in those without antibodies, and the presence of the antibodies together with well-known clinical parameters, including proteinuria and low glomerular filtration rate, was a significant risk factor for end-stage renal disease. In human tubular epithelial HK-2 cells, IgG fractions containing anti-EPOR antibodies upregulated the expression of monocyte chemoattractant protein-1 mRNA under a high concentration of glucose. Conclusion: Anti-EPOR antibodies might be involved in the progression of renal lesions and in the impaired erythropoiesis in type 2 diabetic patients with CKD. Furthermore, the presence of anti-EPOR antibodies may be an additional predictor for end-stage renal disease in type 2 diabetes. © 2017 International Society of Nephrology<br />Embargo Period 12 months
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Koshino, Yoshitaka ; Shinozaki, Yasuyuki ; Wada, Takashi ; 和田, 隆志
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金沢大学医薬保健研究域医学系<br />Embargo Period 12 months
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Mizushima, Ichiro ; Inoue, Dai ; Yamamoto, Motohisa ; Yamada, Kazunori ; Saeki, Takako ; Ubara, Yoshifumi ; Matsui, Shoko ; Masaki, Yasufumi ; Wada, Takashi ; Kasashima, Satomi ; Harada, Kenichi ; Takahashi, Hiroki ; Notohara, Kenji ; Nakanuma, Yasuni ; Umehara, Hisanori ; Yamagishi, Masakazu ; Kawano, Mitsuhiro ; 水島, 伊知郎 ; 井上, 大 ; 山田, 和徳 ; 和田, 隆志 ; 笠島, 里美 ; 原田, 憲一 ; 中沼, 安二 ; 梅原, 久範 ; 山岸, 正和 ; 川野, 充弘
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金沢大学医薬保健研究域医学系<br />Introduction: Immunoglobulin G4 (IgG4)-related aortitis/periaortitis and periarteritis are vascular
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manifestations of IgG4-related disease. In this disease, the affected aneurysmal lesion has been suspected to be at risk of rupture. In this study, we aimed to clarify the clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis.Methods: We retrospectively evaluated clinical features, including laboratory data, imaging findings and the course after corticosteroid therapy, in 40 patients diagnosed with IgG4-related aortitis/periaortitis and periarteritis on the basis of periaortic/periarterial radiological findings, satisfaction of the comprehensive diagnostic criteria or each organ-specific diagnostic criteria, and exclusion of other diseases. Results: The patients were mainly elderly, with an average age of 66.4 years and with a marked male predominance and extensive other organ involvement. Subjective symptoms were scanty, and only a small proportion had elevated serum C-reactive protein levels. The affected aorta/artery were the abdominal aortas or the iliac arteries in most cases. Thirty-six patients were treated with prednisolone, and the periaortic/periarterial lesions improved in most of them during the follow-up period. Two (50.0%) of four patients with luminal dilatation of the affected lesions before corticosteroid therapy had exacerbations of luminal dilatation after therapy, whereas none of the twenty-six patients without it had a new appearance of luminal dilatation after therapy. Conclusions: The results of this retrospective multicenter study highlight three important points: (1) the possibility of latent existence and progression of periaortic/periarterial lesions, (2) the efficacy of corticosteroid therapy in preventing new aneurysm formation in patients without luminal dilatation of periaortic/periarterial lesions and (3) the possibility that a small proportion of patients may actually develop luminal dilatation of periaortic/periarterial lesions in IgG4-related aortitis/periaortitis and periarteritis. A larger-scale prospective study is required to confirm the efficacy and safety of corticosteroid therapy in patients with versus those without luminal dilatation and to devise a more useful and safe treatment strategy, including administration of other immunosuppressants. © 2014 Mizushima et al.; licensee BioMed Central Ltd.
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Zhao, Juanjuan ; Okamoto, Yasuo ; Asano, Yuya ; Ishimaru, Kazuhiro ; Aki, Sho ; Yoshioka, Kazuaki ; Takuwa, Noriko ; Wada, Takashi ; Inagaki, Yutaka ; Takahashi, Chiaki ; Nishiuchi, Takumi ; Takuwa, Yoh ; 安藝, 翔 ; 吉岡, 和晃 ; 多久和, 典子 ; 和田, 隆志 ; 髙橋, 智聡 ; 西内, 巧 ; 多久和, 陽
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金沢大学医薬保健研究域医学系<br />Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of t
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he lysophospholipid mediator sphingosine-1-phosphate and its receptor S1PR2 in lung fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung fibrosis induced by repeated injections of bleomycin in mice. We observed by using S1pr2 LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow–derived cells contributes to the development of lung fibrosis. Depletion of macrophages greatly attenuated lung fibrosis. Bleomycin administration stimulated the mRNA expression of the profibrotic cytokines IL-13 and IL-4 and the M2 markers including arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from bleomycin–administered wild-type mice showed a marked increase in phosphorylation of STAT6, a transcription factor which is activated downstream of IL-13, compared with saline–administered wild-type mice. Interestingly, in bleomycin–adminis-tered S1pr2 -/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2 +/+ mice alleviated bleomycin–induced lung fibrosis. Thus, S1PR2 facilitates lung fibrosis through the mechanisms involving augmentation of IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung fibrosis. © 2018 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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徳丸, 季聡 ; 遠山, 直志 ; 和田, 隆志 ; Tokumasu, Toshiaki ; Toyama, Takashi ; Wada, Takashi
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修士課程優秀論文
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Terakami, Takako ; Sekiya, Akiko ; Hayashi, Kenshi ; Suzuki, Takeshi ; Furusho, Hiroshi ; Asakura, Hidesaku ; Morishita, Eriko ; Wada, Takashi ; 寺上, 貴子 ; 關谷, 暁子 ; 林, 研至 ; 鈴木, 健史 ; 古荘, 浩司 ; 朝倉, 英策 ; 森下, 英理子 ; 和田, 隆志
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[Aim] In this study, the effect of direct oral anticoagulants (DOACs) on protein C (PC) activity was examined using seve
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ral measuring reagents. [Materials and Methods] In total, 90 patients (60 male and ３0 female) with nonvalvular atrial fibrillation or venous thromboembolism (VTE) who were on anticoagulation therapy with DOACs (rivaroxaban, apixaban, or edoxaban) were studied. The plasma levels of PC activity were measured by means of a clotting assay and chromogenic substrate assay, using three reagents for each type of assay. [Result] Prothrombin time (PT) and activated partial thromboplastin time (APTT) were significantly prolonged in a dose-dependent manner in patients who were taking rivaroxaban or edoxaban. PC activity, as measured by all three reagents using the clotting assay, was influenced only by rivaroxaban, indicating an increase in PC activity in a dose-dependent manner. Apixaban did not have any influence on the measurements made using all three reagents in the clotting assay. On the other hand, none of the three FXa inhibitors had any influence on PC activity when it was measured using the three reagents in the chromogenic substrate assay. Plasma samples were collected before, as well as two and four to eight weeks after rivaroxaban administration in seven patients with AF or VTE sequentially. In all three regents using the clotting assay, plasma levels of PC activity had increased after the administration of rivaroxaban. On the other hand, all three regents using the chromogenic assay had very little influence on PC activity after the administration of rivaroxaban. [Conclusion] The inhibitory effects of the different types of DOACs on clotting activity interfere with clotting test measurement systems in patients receiving DOAC therapy. When measuring PC activity while the patient is taking rivaroxaban or edoxaban, it is necessary to use the chromogenic substrate assay to avoid false highs. Moreover, collecting specimens when blood levels of drugs are low, e.g. during the trough phase, whenever possible, would be one way to minimize interference.
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Iwata, Yasunori ; Wada, Takashi ; Yokoyama, Hitoshi ; Toyama, Tadashi ; Kitajima, Shinji ; Okumura, Toshiya ; Hara, Akinori ; Yamahana, Junya ; Nakaya, Izaya ; Kobayashi, Motoo ; Kitagawa, Kiyoki ; Kokubo, Satoshi ; Yoshimoto, Keiichi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Furuichi, Kengo ; Koshino, Yoshitaka ; Takaeda, Chikako ; Takeda, Shinichi ; Takasawa, Kazuya ; Ohta, Satoshi ; Takaeda, Masayoshi ; Kaneko, Shuichi
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金沢大学保健管理センター<br />金沢大学大学院医学系研究科<br />金沢大学附属病院<br />Background: In hemodialysis patients, adynamic bone disease has been
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reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. Methods: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). Results: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31±18 pg/mL to 95±96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. Conclusion: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes. © 2007 The Japanese Society of Internal Medicine.
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Iwata, Yasunori ; Wada, Takashi ; Furuichi, Kengo ; Kitagawa, Kiyoki ; Kokubo, Satoshi ; Kobayashi, Motoo ; Sakai, Norihiko ; Yoshimoto, Keiichi ; Shimizu, Miho ; Kobayashi, Kenichi ; Yokoyama, Hitoshi
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金沢大学医薬保健研究域医学系<br />Objective. KL-6 is reported to be excreted from the lung alveolar and bronchial epithelial cells and
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may be a good marker for monitoring disease activity of interstitial pneumonia. This study was designed to ascertain the clinical significance of serum KL-6 levels in interstitial pneumonia associated with anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis. Methods. Serum KL-6 levels were determined by an enzyme-linked immunosorbent assay. Patients. We examined 20 healthy subjects, 13 patients with perinuclear (myeloperoxidase, MPO) ANCA-related vasculitis and 12 dermatomyositis (DM)/polymyositis (PM) patients as disease controls in this study. Six out of 13 patients with ANCA-related vasculitis had interstitial pneumonia. Results. Serum levels of KL-6 in ANCA-positive patients with interstitial pneumonia were significantly elevated, while they remained as low as those of healthy subjects in ANCA- positive patients without interstitial pneumonia. Similarly, KL-6 levels in sera were higher in 12 dermatomyositis/polymyositis patients with interstitial pneumonia, while they remained low in DM/PM patients without interstitial pneumonia. Moreover, the elevated serum KL-6 level was reduced during the convalescence induced by glucocorticoid therapy and reflected the disease activity of interstitial pneumonia associated with ANCA-related vasculitis. Conclusion. These data suggest that the measurement of serum KL-6 levels may be a good monitoring system for the diagnosis and follow-up of interstitial pneumonia of patients with ANCA-related vasculitis.
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Sakai, Norihiko ; Furuichi, Kengo ; Shinozaki, Yasuyuki ; Yamauchi, Hiroyuki ; Toyama, Tadashi ; Kitajima, Shinji ; Okumura, Toshiya ; Kokubo, Satoshi ; Kobayashi, Motoo ; Takasawa, Kazuya ; Takeda, Shin-ichi ; Yoshimura, Mitsuhiro ; Kaneko, Shuichi ; Wada, Takashi
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金沢大学医薬保健研究域医学系<br />The presence of chronic kidney disease in humans is associated with a risk of kidney function loss a
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s well as the development of cardiovascular disease. Fibrocytes have been shown to contribute to organ fibrosis. In this study, the presence of fibrocytes was investigated immunohistochemically in kidney biopsy specimens from 100 patients with chronic kidney disease. In addition, 6 patients with thin basement membrane disease were studied as a disease control. In patients with chronic kidney disease, the infiltration of fibrocytes was observed mainly in the interstitium. The number of interstitial fibrocytes in patients with chronic kidney disease was higher than that in patients with thin basement membrane disease. The number of infiltrated fibrocytes in the interstitium correlated well with the severity of tubulointerstitial lesions, such as interstitial fibrosis, in patients with chronic kidney disease. In addition, there were significant correlations between the number of interstitial fibrocytes and the number of CD68-positive macrophages in the interstitium as well as urinary monocyte chemoattractant protein-1/CCL2 levels. In particular, there was an inverse correlation between the number of interstitial fibrocytes and kidney function at the time of biopsy. Finally, the numbers of interstitial fibrocytes and macrophages as well as urinary CCL2 levels were significantly decreased during convalescence induced by glucocorticoid therapy. These results suggest that fibrocytes may be involved in the pathogenesis of chronic kidney disease through the interaction with macrophages as well as CCL2. © 2010 Elsevier Inc. All rights reserved.
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Shindo, Takayuki ; Kurihara, Hiroki ; Kuno, Kouji ; Yokoyama, Hitoshi ; Wada, Takashi ; Kurihara, Yukiko ; Imai, Tomihiko ; Wang, Yuhui ; Ogata, Masafumi ; Nishimatsu, Hiroaki ; Moriyama, Nobuo ; Oh-hashi, Yoshio ; Morita, Hiroyuki ; Ishikawa, Takatoshi ; Nagai, Ryozo ; Yazaki, Yoshio ; Matsushima, Kouji
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金沢大学医薬保健研究域医学系<br />A disintegrin and metalloproteinase (ADAM) represents a protein family possessing both metalloprotei
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nase and disintegrin domains. ADAMTS-1, an ADAM family member cloned from cachexigenic colon adenocarcinoma, is unusual in that it contains thrombospondin type I motifs and anchors to the extracellular matrix. To elucidate the biological role of ADAMTS-1, we developed ADAMTS-1-null mice by gene targeting. Targeted disruption of the mouse ADAMTS-1 gene resulted in growth retardation with adipose tissue malformation. Impaired female fertilization accompanied by histological changes in the uterus and ovaries also resulted. Furthermore, ADAMTS-1(-/-) mice demonstrated enlarged renal calices with fibrotic changes from the ureteropelvic junction through the ureter, and abnormal adrenal medullary architecture without capillary formation. ADAMTS-1 thus appears necessary for normal growth, fertility, and organ morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease.
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Menke, Julia ; Iwata, Yasunori ; Rabacal, Whitney A. ; Basu, Ranu ; Yeung, Yee G. ; Humphreys, Benjamin D. ; Wada, Takashi ; Schwarting, Andreas ; Stanley, E. Richard ; Kelley, Vicki R.
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金沢大学医薬保健研究域医学系<br />Tubular damage following ischemic renal injury is often reversible, and tubular epithelial cell (TEC
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) proliferation is a hallmark of tubular repair. Macrophages have been implicated in tissue repair, and CSF-1, the principal macrophage growth factor, is expressed by TECs. We therefore tested the hypothesis that CSF-1 is central to tubular repair using an acute renal injury and repair model, ischemia/reperfusion (I/R). Mice injected with CSF-1 following I/R exhibited hastened healing, as evidenced by decreased tubular pathology, reduced fibrosis, and improved renal function. Notably, CSF-1 treatment increased TEC proliferation and reduced TEC apoptosis. Moreover, administration of a CSF-1 receptor-specific (CSF-1R-specific) antibody after I/R increased tubular pathology and fibrosis, suppressed TEC proliferation, and heightened TEC apoptosis. To determine the contribution of macrophages to CSF-1-dependent renal repair, we assessed the effect of CSF-1 on I/R in mice in which CD11b + cells were genetically ablated and determined that macrophages only partially accounted for CSF-1-dependent tubular repair. We found that TECs expressed the CSF-1R and that this receptor was upregulated and coexpressed with CSF-1 in TECs following renal injury in mice and humans. Furthermore, signaling via the CSF-1R stimulated proliferation and reduced apoptosis in human and mouse TECs. Taken together, these data suggest that CSF-1 mediates renal repair by both a macrophage-dependent mechanism and direct autocrine/paracrine action on TECs.
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Iwata, Yasunori ; Wada, Takashi ; Uchiyama, Akio ; Miwa, Atsuo ; Nakaya, Izaya ; Tohyama, Tadashi ; Yamada, Yuhji ; Kurokawa, Toshiro ; Yoshida, Takashi ; Ohta, Satoshi ; Yokoyama, Hitoshi ; Iida, Hiroyuki
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金沢大学医薬保健研究域医学系<br />We report a case with immunoglobulin A (IgA) nephropathy, showing IgA deposition which disappeared a
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fter peripheral blood stem cell transplantation (PBSCT) for acute lymphocytic leukemia (ALL). In 1996, a 28-year-old man was diagnosed with IgA nephropathy by renal biopsy. Steroid therapy improved proteinuria from 3 g/day to 1 g/day. In 2003, he received PBSCT following the initial therapy for ALL. After complete remission, urinary protein and hematuria remained at between (-) and (±). In 2004, the second renal biopsy specimen revealed no deposit of IgA or C3. These findings suggested that immune reconstruction with PBSCT following immunosuppression therapy was of benefit to IgA nephropathy. © 2006 The Japanese Society of Internal Medicine.
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| 17.
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Wada, Takashi ; Sakai, Norihiko ; Sakai, Yoshio ; Matsushima, Kouji ; Kaneko, Shuichi ; Furuichi, Kengo
概要:
金沢大学医薬保健研究域医学系<br />Cellular mechanisms have been proposed in the pathogenesis of fibrotic processes in the kidney. In t
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his setting, cell sources underlying the generation of matrix-producing cells in diseased kidneys have been categorized as activated resident stromal cells (e.g., fibroblasts, pericytes), infiltrating bone-marrow-derived cells (e.g., fibrocytes, T cells, macrophages), and cells derived from epithelial-mesenchymal transition/endothelial-mesenchymal transition. Among these cell sources, accumulating evidence has shed light on the involvement of bone-marrow-derived cells, including monocytes/macrophages, and a circulating mesenchymal progenitor cell, fibrocyte, in the progression of fibrosis in kidney. Bone-marrow-derived cells positive for CD45 or CD34, and type 1 (pro)collagen dependent on the chemokine and renin-angiotensin systems migrate into diseased kidneys and enhance synthesis matrix protein, cytokines/chemokines, and profibrotic growth factors, which may promote and escalate chronic inflammatory processes and possible interaction with resident stromal cells, thereby perpetuating kidney fibrosis. © 2010 Japanese Society of Nephrology.
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| 18.
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Iwata, Yasunori ; Furuichi, Kengo ; Kitagawa, Kiyoki ; Hara, Akinori ; Okumura, Toshiya ; Kokubo, Satoshi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Sagara, Akihiro ; Kurokawa, Yukie ; Ueha, Satoshi ; Matsushima, Satoshi ; Kaneko, Shuichi ; Wada, Takashi
概要:
金沢大学医薬保健研究域医学系<br />Objective: Myeloid-derived suppressor cells (MDSCs) have been identified as immunosuppressive cells
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in tumor-related inflammation. However, the pathogenesis of MDSCs for autoimmune disease has not been investigated as yet. The aim of this study was to address whether MDSCs contribute to autoimmune organ injury in lupus-prone mice. Methods: MDSCs were analyzed by flow cytometric staining of CD11b+ GR-1+ in MRL-Faslpr mice. CD4+ T-cell proliferation assay was performed by coculture with CD11b+ GR-1+ splenocytes. The percentage of immunosuppressive cells was examined during disease progression. Expression of chemokine receptor on immunosuppressive cells was analyzed, and chemotaxis assay was performed. Results: CD11b+ GR-1low cells had a suppressive effect on CD4+ T-cell proliferation, which was restored by an arginase-1 inhibitor. CD11b+ GR-1low cells increased in percentage during disease progression in kidney and blood. The number of migrated CD11b+ GR-1low cells increased in the presence of monocyte chemoattractant protein-1/CCL2. Conclusion: We assessed the involvement of CD11b+ GR-1low cells in autoimmune disorder in MRL-Faslpr mice. These cells regulate immunological responses via CCL2/CCR2 signaling. The regulation of immunosuppressive monocytes may provide novel therapeutic strategy for organ damage in autoimmune diseases. © 2010 Japanese Society of Nephrology..
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| 19.
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Wada, Takashi ; Tomosugi, Naohisa I. ; Naito, Takero ; Yokoyama, Hitoshi ; Kobayashi, Kenichi ; Harada, Akihisa ; Mukaida, Naofumi ; Matsushima, Kouji
概要:
Glomerular infiltration by neutrophils is a hallmark of acute glomerulonephritis. The pathophysiological role of interle
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ukin 8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), was explored in an animal model of acute immune complex-mediated glomerulonephritis by administering a neutralizing antibody against IL-8. Repeated injection of bovine serum albumin (BSA) into rabbits caused the deposition of immune complexes consisting of BSA and rabbit IgG in glomeruli. Histological analyses revealed a small but significant number of neutrophils in glomeruli and the fusion of epithelial cell foot processes. Concomitantly, urinary levels of protein and albumin increased markedly (3.20 ± 0.97 and 1.39 ± 0.53 mg/h, respectively) compared with those of untreated animals (0.77 ± 0.21 and 0.01 ± 0.01 mg/h, respectively). Anti-IL-8 antibody treatment decreased the number of neutrophils in glomeruli by 40% and dramatically prevented the fusion of epithelial cell foot process. Furthermore, treatment with anti-IL-8 antibody completely normalized the urinary levels of protein and albumin (0.89 ± 0.15 and 0.02 ± 0.01 mg/h, respectively). These results indicated that IL-8 participated in the impairment of renal functions in experimental acute immune complex-mediated glomerulonephritis through activating as well as recruiting neutrophils.
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| 20.
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Wada, Takashi ; Shimizu, Miho ; Toyama, Tadashi ; Hara, Akinori ; Kaneko, Shuichi ; Furuichi, Kengo
概要:
金沢大学医薬保健研究域医学系<br />Patients suffering from diabetic nephropathy, resulting in end-stage renal failure, are increasing i
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n number. The pathophysiology of diabetic nephropathy remains to be fully investigated. In the clinical setting, the presence of albuminuria/overt proteinuria and a low glomerular filtration rate may predict poor renal prognosis, but the prognosis of the normoalbuminuric renally insufficient diabetic patient remains controversial. In addition to the measurement of urinary albumin excretion, biomarker studies to detect diabetic nephropathy more specifically at the early stage have been performed worldwide. There is a growing body of evidence for remission and/or regression of diabetic nephropathy, which may be an indicator for cardiovascular and renal risk reduction. Deeper insights into the pathological characteristics as well as the clinical impact of albuminuria on renal and cardiovascular outcome are required. © 2011 Japanese Society of Nephrology.
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| 21.
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Wada, Takashi ; Yokoyama, Hitoshi ; Sakai, Norihiko ; Izumiya, Yoshiaki ; Shimizu, Miho ; Furuichi, Kengo ; Segawa, Chikako ; Misaki, Tsuguho ; Kobayashi, Ken-ichi
概要:
We describe the upregulation of cytokines in a 45-year-old woman with tubulointerstitial nephritis and membranous nephro
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pathy revealed by renal biopsy. She was treated with a combination of prednisolone and cyclosporin. Histological findings showed appreciable improvement, and urinary protein excretion was decreased from 15 g/day to 1 g/day. Elevated urinary levels of chemokines, interleukin (IL)-8 and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein (MCP)-1, and serum levels of tumor necrosis factor (TNF)-α decreased during convalescence; 13 other patients with membranous nephropathy did not show elevation of these cytokines. These results suggest that the upregulation of these cytokines may participate in the pathogenesis of tubulointerstitial nephritis and that combination therapy of prednisolone and cyclosporin may be effective, possibly via inducing a decrease in these cytokines.
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| 22.
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Ohta, Satoshi ; Yokoyama, Hitoshi ; Ise, Takuyuki ; Takasawa, Kazuya ; Wada, Takashi ; Nakao, Sinji ; Matsuda, Tamotsu ; Kobayashi, Ken-ichi
概要:
Two cases of leukemia were treated successfully with apheresis for delayed recovery of erythropoiesis due to antibody-mediated red cell aplasia after ABO-mismatched bone marrow transplantation (BMT). A 25-year-old female (ABO
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group O) underwent BMT from her brother (group A). Immunoadsorption using Biosynsorb A performed on day 146 after BMT followed by double filtration plasma pheresis (DFPP) reduced anti-A antibody titers from 1:32 to 1:2. Anemia improved dramatically within 2 weeks. A 49-year-old female (group O) underwent BMT from her mother (group A). She was treated with DFPP on day 131 after BMT. Anti-A antibody titers dropped from 1:16 to 1:1 and anemia improved gradually.
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| 23.
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Kitajima, Shinji ; Sakai, Norihiko ; Furuichi, Kengo ; Tomokage, Miki ; Hara, Akinori ; Kitagawa, Kiyoki ; Sawada-Kitamura, Seiko ; Zen, Yoh ; Nakada, Mitsutoshi ; Kaneko, Shuichi ; Wada, Takashi
概要:
金沢大学医薬保健研究域医学系<br />We described a case of neurosarcoidosis with necrotizing sarcoid granulomatosis in a 22-year-old man
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. Contrast-enhanced brain computed tomography scan and magnetic resonance imaging showed intracerebral multiple nodular lesions. Noncaseating and partial necrotizing granulomas were detected in the specimen resected by neurosurgery. In addition, immunohistochemical examination revealed the expression of angiotensin-converting enzyme in necrotizing granuloma. Thus, these findings were consistent with neurosarcoidosis. Clinical and pathological presentation, immunological features, and treatment modalities of neurosarcoidosis are discussed. © 2010 Japan College of Rheumatology.<br />This is the pre-peer reviewed version of the following article: [Full cite], which has been published in final form at [link to final article].
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| 24.
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Oshima, Megumi ; Kitajima, Shinji ; Toyama, Tadashi ; Hara, Akinori ; Kitagawa, Kiyoki ; Iwata, Yasunori ; Shimizu, Miho ; Nishio, Saori ; Imura, Junko ; Yokoyama, Hitoshi ; Furuichi, Kengo ; Kaneko, Shuichi ; Wada, Takashi
概要:
We herein report a case of spontaneous pregnancy and preterm delivery in a 29-year-old patient with myeloperoxidase-anti
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neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Her basal serum creatinine level before pregnancy was 1.4 mg/dL and her urinary protein level was approximately 2 g/day. The proteinuria and hematuria increased during pregnancy, and the patient was admitted to our hospital and treated with prednisolone (PSL). At 27 weeks of gestation, she delivered a live infant weighing 848 g via cesarean section. No relapse of ANCA-associated glomerulonephritis occurred. © 2013 The Japanese Society of Internal Medicine.
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| 25.
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Yokoyama, Hitoshi ; Wada, Takashi ; Zhang, Wei ; Yamaya, Hideki ; Asaka, Mitsuhiro
概要:
This article is an overview of the immunomodulatory effects of apheresis in renal diseases, especially primary and secon
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dary glomerulonephritis, and the clinical evidence for the efficacy of apheresis therapy. Permeability factor(s) derived from circulating T cells are speculated to have a crucial role in the proteinuria of nephrotic syndrome (NS). Plasma exchange (PE); immunoadsorption plasmapheresis (IAPP), using protein A sepharose cartridges; low-density lipoprotein apheresis; and lymphocytapheresis (LCAP) have been used to remove such factors or pathogenic T cells. Other glomerular diseases induced by specific antibodies such as anti-glomerular basement membrane antibodies, anti-neutrophil cytoplasmic antibodies, and immune-complexes have also been treated with PE, double-filtration plasmapheresis, IAPP, and LCAP. Recommendations, based on the evidence from recent randomized controlled studies, have been established in apheresis therapy for various glomerular diseases. © 2007 Japanese Society of Nephrology.
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| 26.
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Nakade, Yusuke ; Fujimura, Masaki ; Ohkura, Noriyuki ; Nakata, Masako ; Nanbu, Yuko ; Oe, Hiroyasu ; Horita, Hiroshi ; Sakai, Yoshio ; Wada, Takashi
概要:
Objective Partial expiratory flow-volume curves have the potential to detect mild bronchoconstriction because they are n
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ot affected by the modulatory effects of deep inspiration. The aim of this study was to investigate the relationship between the efficacy of bronchodilator therapy (BDT) in treating the cough and to assess the increase in the expiratory flow of the partial flow-volume curve at 40% above the residual volume level (PEF40) caused by treatment with a short-acting beta-2 agonist (SABA) in patients with chronic nonproductive cough. Methods We measured the reversibility of PEF40 caused by a SABA in 42 patients with chronic nonproductive cough at visit 1 (day 0). The patients received BDT for six days. The visual analogue scale (VAS) was used to assess the efficacy of BDT in treating coughing at visit 2 (day 7) (0 mm, 'no cough;' 100 mm, 'no change in coughing'). Results Reversibility of the PEF40 was correlated (r=0.690, p<0.001) with the VAS score determined at visit 2 and was higher in the patients with cough variant asthma (CVA) (44.9±18.3%) than in those with atopic cough (13.4±10.4%) (p<0.01). Conclusion Reversibility of the PEF40 predicted the efficacy of BDT in patients with chronic nonproductive cough and helped to identify patients with CVA.
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| 27.
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Iwata, Yasunori ; Furuichi, Kengo ; Kaneko, Shuichi ; Wada, Takashi
概要:
Lupus nephritis (LN) is a major clinical manifestation of systemic lupus erythematosus (SLE). Although numerous abnormal
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ities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mψ) and dendritic cells (DCs), secrete a variety of cytokines and activate nave T cells, leading the cytokine profile towards T helper (Th)1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN. © 2011 Yasunori Iwata et al.
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| 28.
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Nakade, Yusuke ; Takamura, Toshinari ; Sakurai, Masaru ; Misu, Hirofumi ; Nagata, Mitsuko ; Nanbu, Yuko ; Oe, Hiroyasu ; Takamura, Toshiji ; Sakai, Yoshio ; Kaneko, Shuichi ; Wada, Takashi
概要:
The aim of the present study was to examine whether there is a relationship between autonomic function and post-challeng
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e hyperglycemia in patients with type 2 diabetes. Subjects included 122 Japanese patients newly diagnosed with type 2 diabetes. Autonomic nerve function was assessed using coefficients of variation of the R-R intervals on electrocardiograms (CVRR). Unlike anthropometry, insulin secretion and insulin resistance, age (r =)0.209, P < 0.021) and post-challenge plasma glucose at 120 min (PG120; r =)0.219, P < 0.015) were the only variables significantly correlated with CVRR. Age was not significantly correlated with PG120. In multiple regression analyses, CVRR Z-score, but not age, was significantly correlated with PG120. The present results suggest that autonomic function affects post-challenge blood glucose levels independently of age. © 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd.
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| 29.
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Hara, Akinori ; Wada, Takashi ; Kitajima, Shinji ; Toyama, Tadashi ; Okumura, Toshiya ; Kitagawa, Kiyoki ; Iwata, Yasunori ; Sakai, Norihiko ; Furuichi, Kengo ; Higuchi, Masato ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />A 42-year-old woman with systemic lupus erythematosus was admitted to our hospital because of severe
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anemia. Her bone marrow was almost normocellular and erythroblasts were nearly absent. Laboratory data showed elevated levels of lactate dehydrogenase and positive findings on Coombs' tests. On the basis of these findings, her anemia was diagnosed as the overlap of pure red cell aplasia with autoimmune hemolytic anemia. Radioimmunoprecipitation assay revealed that her serum was positive for anti-erythropoietin antibodies before therapy. Furthermore, the autoantibodies inhibited proliferation of an erythropoietin-dependent cell line in a dose-dependent manner. Immunosuppressive treatment improved the anemia accompanied with disappearance of the autoantibodies. © 2008 Wiley-Liss, Inc.
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| 30.
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Wada, Takashi ; Haneda, Masakazu ; Furuichi, Kengo ; Babazono, Tetsuya ; Yokoyama, Hiroki ; Iseki, Kunitoshi ; Araki, Shin-ichi ; Ninomiya, Toshiharu ; Hara, Shigeko ; Suzuki, Yoshiki ; Iwano, Masayuki ; Kusano, Eiji ; Moriya, Tatsumi ; Satoh, Hiroaki ; Nakamura, Hiroyuki ; Shimizu, Miho ; Toyama, Tadashi ; Hara, Akinori ; Makino, Hirofumi
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| 31.
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Wada, Takashi ; Haneda, Masakazu ; Furuichi, Kengo ; Babazono, Tetsuya ; Yokoyama, Hiroki ; Iseki, Kunitoshi ; Araki, Shin-ichi ; Ninomiya, Toshiharu ; Hara, Shigeko ; Suzuki, Yoshiki ; Iwano, Masayuki ; Kusano, Eiji ; Moriya, Tatsumi ; Satoh, Hiroaki ; Nakamura, Hiroyuki ; Shimizu, Miho ; Toyama, Tadashi ; Hara, Akinori ; Makino, Hirofumi
概要:
Background: The number of patients suffering from diabetic nephropathy resulting in end-stage kidney disease is increasi
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ng worldwide. In clinical settings, there are limited data regarding the impact of the urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR) on renal and cardiovascular outcomes and all-cause mortality. Methods: We performed a historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers. Risks for renal events (requirement for dialysis or transplantation, or half reduction in eGFR), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), and all-cause mortality were assessed according to UACR and eGFR levels. Results: During follow-up (median 7.0 years, interquartile range 3.0-8.0 years), 419 renal events, 605 cardiovascular events and 236 deaths occurred. The UACR levels increased the risk and the adjusted hazard ratios for these three events. In addition to the effects of UACR levels, eGFR stages significantly increased the adjusted hazard ratios for renal events and all-cause mortality, especially in patients with macroalbuminuria. Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for each event. Conclusions: Increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality in Japanese patients with type 2 diabetes, whereas the association between high levels of UACR and reduced eGFR was a strong predictor for renal events. © 2013 Japanese Society of Nephrology.
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| 32.
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Toyama, Tadashi ; Shimizu, Miho ; Furuichi, Kengo ; Kaneko, Shuichi ; Wada, Takashi ; 清水, 美保 ; 古市, 賢吾 ; 金子, 周一 ; 和田, 隆志
概要:
Recent epidemiological research revealed that dyslipidemia is a risk factor for development and progression of diabetic
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nephropathy. Results from interventional studies revealed the possibility that anti-hyperlipidemic agents have a better effect on diabetic nephropathy through improvement of albuminuria and loss of renal function. In addition, dyslipidemia may be a consequence of albuminuria and renal dysfunction, thereby perpetuating kidney damage. Today, the proportion of diabetic patients receiving statins is increasing due to their beneficial effect on cardiovascular mortality. However, treatment for patients should be determined based on consideration of the risk and benefit of the treatment. More insight into the pathogenesis of diabetic nephropathy and the effects of life-style changes is required. © 2013 Japanese Society of Nephrology.
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| 33.
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Sakai, Norihiko ; Furuichi, Kengo ; Wada, Takashi
概要:
Inflammasomes are important components of innate immunity system. Dysregulation of inflammasomes activation is central t
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o the pathogenesis of inflammatory diseases. The measurement of inflammasomes activity especially in in vivo settings should give us important information to regulate inflammatory events. Ludwig-Portugall et al. clearly visualized the intrarenal activation of inflammasome in a murine model of crystal nephropathy using a proteolytic luciferase-based reporter, and showed that the blockade of NLRP3 inflammasome may prevent renal injuries. © 2016 International Society of Nephrology<br />Embargo Period 12 months
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| 34.
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Toyama, Tadashi ; Furuichi, Kengo ; Shimizu, Miho ; Hara, Akinori ; Iwata, Yasunori ; Sakai, Norihiko ; Perkovic, Vlado ; Kobayashi, Makoto ; Mano, Toshiki ; Kaneko, Shuichi ; Wada, Takashi
概要:
Background: Some observational studies have shown the relationships between hyperuricemia and chronic kidney disease (CK
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D); however, the threshold of serum uric acid (SUA) for deterioration of kidney function and the association between SUA and kidney injury by baseline kidney function remains unclear. This study aimed to clarify the relationships between SUA and reduced kidney function. Methods: We analyzed a historical cohort of male Japanese individuals who underwent medical checkup between 1998 and 2007. Participants with baseline data and who were followed up for at least one year were included and stratified according to baseline kidney function. Kidney function was classified as normal [estimated glomerular filtration rate (eGFR) ≥ 90 ml/min/1.73 m2] or mildly reduced (eGFR 60-89 ml/min/1.73 m2). The outcome measured was kidney impairment defined as a decrease in eGFR to < 60 ml/min/1.73 m2. Associations between SUA and risk for outcome and eGFR slopes were assessed. Results: A total of 41632 subjects with mean age 45.4 years were included. During a mean follow-up of four years, 3186 (7.6%) subjects developed kidney dysfunction. Subjects with SUA ≥ 6.0 mg/dL had a significantly increased risk for kidney impairment compared with subjects with SUA of 4-4.9 mg/dL. SUA threshold levels were different according to baseline kidney function; SUA ≤ 7.0 and ≤ 6.0 mg/dL for normal and mildly reduced kidney function, respectively. Approximately the same trends were observed for eGFR slopes. Conclusion: In the general population, hyperuricemia appears to be a risk factor for kidney impairment in males. For participants with mild kidney dysfunction, even a slight elevation of SUA can be a risk factor. Copyright: © 2015 Toyama et al.<br />This article has a supplementary figure. Please see the last page of the text.
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| 35.
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Yamashita, Tatsuya ; Arai, Kuniaki ; Sakai, Akito ; Mizukoshi, Eishiro ; Sakai, Yoshio ; Kagaya, Takashi ; Nakamoto, Yasunari ; Honda, Masao ; Wada, Takashi ; Yokoyama, Hitoshi ; Kaneko, Shuichi
概要:
金沢大学医学部附属病院内科<br />Purpose: In patients with chronic genotype 1b hepatitis C and a high viral load, the viral load was r
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educed by double filtration plasmapheresis (DFPP), followed by combined interferon and ribavirin therapy. The safety and virological effects of this treatment method were preliminarily investigated. Methods: In nine patients with chronic hepatitis C, DFPP was performed three times on days 1, 2, and 4, and the administration of interferon and ribavirin was initiated immediately after DFPP on day 1. Result: The HCV RNA was undetectable in all patients after the plasma was passed through a plasma fractionator (second filter) in the DFPP circuit. After 2 weeks, the HCV RNA tended to decrease in the DFPP group more than in the control group (-2.45 ± 1.12 versus -1.57 ± 0.95, P = 0.073). However, this decrease was not attributable to a sustained virological response (SVR) (22.2% versus 18.2%, P = 0.822). Most of the adverse events were caused by the interferon and ribavirin combination therapy. Conclusion: DFPP can be safely performed concomitantly with interferon and ribavirin combination therapy in chronic hepatitis C patients. The combination may contribute to an early virological response. The effect of DFPP on the SVR and its significance remain to be clarified. © 2006 Elsevier Ireland Ltd. All rights reserved.
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| 36.
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Wada, Takashi ; Sakai, Norihiko ; Matsushima, Kouji ; Kaneko, Shuichi
概要:
金沢大学医学部附属病院血液浄化療法部<br />Fibrocytes are supposed to be a circulating connective tissue cell progenitor, which consists of
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a novel population of peripheral blood cells. This distinct population of blood-borne cells shares markers of leukocytes as well as mesenchymal cells. Accumulating evidence indicates that fibrosis is characteristic of progressive chronic kidney diseases of any etiologies, resulting in kidney failure. We have uncovered that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to kidney fibrosis induced by unilateral ureteral obstruction in mice. In addition, the blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced kidney fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in macrophage recruitment along with reduced renal transcripts of monocyte chemoattractant protein-1 (MCP-1/CCL2). These findings suggest that fibrocytes dependent on CCL21/CCR7 signaling pathways contribute to the pathogenesis of kidney fibrosis, thereby providing that regulating fibrocytes may provide a novel therapeutic benefit for kidney fibrosis. © 2007 International Society of Nephrology.
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| 37.
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Wada, Takashi ; Yokoyama, Hitoshi ; Matsushima, Koji ; Kobayashi, Kenichi ; 和田, 隆志
概要:
The interaction of activated leukocytes and renal resident cells is thought to play a crucial role in the pathogenesis of renal diseases. Recent investigations of the pathophysiological roles of chemokines and their cognate receptors have
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shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in the diseased kidneys. Chemokine/chemokine receptor systems may be essentially involved in the pathogenesis of phase-specific renal disorders and the measurement of urinary levels of chemokines may be clinically useful for monitoring the different disease phases and activities. In addition, chemokine receptors expressed in renal resident cells may be involved in proliferation, fibrogenesis, as well as chemotaxis. The selective intervention of chemokine/chemokine receptor systems (anti-chemokine therapy) may have the potential as the particular therapeutic strategies for renal diseases in future
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| 38.
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論文
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Yamahana, Junya ; Wada, Takashi ; Furuichi, Kengo ; Yokoyama, Hitoshi ; Kaneko, Shuichi
概要:
金沢大学医学部附属病院血液浄化療法部<br />Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that maintains the glome
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rular and peritubular capillary (PTC) network in the kidney. The soluble form of the VEGF receptor-1 (soluble fms-like tyrosine kinase 1 (sFlt-1)) is known to regulate VEGF activity by binding VEGF in the circulation. We hypothesized that VEGF may be beneficial for maintaining glomerular filtration barrier and vascular network in rats with progressive glomerulonephritis (GN). For blockade of VEGF activity in vivo, rats were transfected twice with plasmid DNA encoding the murine sFlt-1 gene into femoral muscle 3 days before and 2 weeks after the induction of antiglomerular basement membrane antibody-induced GN. Inhibition of VEGF with sFlt-1 resulted in massive urinary protein excretion, concomitantly with downregulated expression of nephrin in nephritic rats. Further, blockade of VEGF induced mild proteinuria in normal rats. Administration of sFlt-1 affected neither the infiltration of macrophages nor crescentic formation. In contrast, treatment of sFlt-1 accelerated the progression of glomerulosclerosis and interstitial fibrosis accompanied with renal dysfunction and PTC loss at day 56. VEGF may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults. ﾂｩ 2006 International Society of Nephrology.
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| 39.
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Mitsuyama, Hideo ; Matsuyama, Wataru ; Watanabe, Masaki ; Shirahama, Yuko ; Higashimoto, Ikkou ; Wada, Takashi ; Osame, Mitsuhiro ; Arimura, Kimiyoshi
概要:
金沢大学医学部附属病院血液浄化療法部<br />Objective. Prolonged survival of eosinophils plays au important role in the pathogenesis of Chur
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g-Strauss syndrome (CSS); however, its detailed molecular mechanism is still unclear. TRAIL and its receptors are expressed on a variety of cells, including eosinophils. In this study, we examined the expression of TRAIL receptors on eosinophils from patients with CSS. Methods. TRAIL receptor expression was assessed on eosinophils from healthy volunteers, patients with CSS, patients with asthma, and patients with hypereosinophilia due to parasitic infection. TRAIL-induced apoptosis of eosinophils was compared between the patients with CSS and patients with asthma. RNA interference was used to assess the effects of suppression of TRAIL receptor 3. Results. Expression of TRAIL receptor 3, a decoy receptor that acts as an antiapoptotic receptor, on eosinophils from patients with CSS was significantly higher than that in the other subjects. Moreover, in CSS, serum TRAIL receptor 3 levels showed a significant positive correlation with peripheral eosinophil counts, tissue-infiltrating eosinophils stained positive for this receptor, and peripheral T cells expressed TRAIL on their surface. Compared with asthma patients, eosinophils from CSS patients showed a significantly lower percentage of recombinant TRAIL, less autologous T cell-induced apoptosis, and decreased level of active caspase 3. Suppression of TRAIL receptor 3 through RNA interference significantly increased the recombinant TRAIL-induced apoptosis of eosinophils from CSS patients. Conclusion. Increased expression of TRAIL receptor 3 on eosinophils from patients with CSS was observed. These alterations in TRAIL receptor 3 expression might be involved in the molecular pathogenesis of CSS eosinophilia. © 2007, American College of Rheumatology.
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| 40.
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論文
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Yamahana, Junya ; Wada, Takashi ; Yokoyama, Hitoshi ; Kaneko, Shuichi ; Furuichi, Kengo
概要:
金沢大学医学部附属病院血液浄化療法部<br />Background. The therapeutic efficacy of the regulation of T helper (Th)-1-predominant immune res
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ponses remains to be investigated. Therefore, the effects of the anti-inflammatory compound TAK-603 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar-Kyoto rats. Methods. TAK-603 (50 mg/kg body weight) was administered orally, starting at the time of induction of glomerulonephritis. In group 1, the drug was administered daily for the initial 6 days. TAK-603 was administered on day 0 only in group 2, and from day 3 to 5 in group 3. In each group, nephritic rats were killed on days 6 and 56. Results. In group 1 consisting of rats treated with TAK-603 daily from day 0 to 5, glomerular damage, including crescent formation, was improved on day 6, with reductions in the numbers of CD4, CD8 and ED-1 positive cells, as well as in urinary protein excretion. Protein and transcript levels of Th1 cytokines in the diseased kidneys were markedly decreased by TAK-603 treatment. Renal pathology, including glomerulosclerosis and interstitial fibrosis, was ameliorated and proteinuria was markedly decreased. Elevated levels of serum creatinine showed concomitant improvement. In group 3, in which treatment was initiated shortly after the appearance of glomerular abnormalities, glomerular damage was also diminished, resulting in a decrease in urinary protein excretion. Treatment only on the first day in group 2, partially rescued renal dysfunction. Conclusions. These results suggest the possible therapeutic application of inhibition of Th1-predominant immune responses in progressive crescentic glomerulosclerosis. © 2006 Oxford University Press.
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Toyama, Tadashi ; Furuichi, Kengo ; Ninomiya, Toshiharu ; Shimizu, Miho ; Hara, Akinori ; Iwata, Yasunori ; Kaneko, Shuichi ; Wada, Takashi
概要:
Background:Precise effects of albuminuria and low estimated glomerular filtration rate (eGFR) on cardiovascular mortalit
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y, all-cause mortality, and renal events in diabetic patients are uncertain.Materials and Methods:A systematic review was conducted of the literature through MEDLINE, EMBASE, and CINHAL from 1950 to December 2010. Cohort studies of diabetic patients providing adjusted relative risk (RR) of albuminuria and eGFR for risks of cardiovascular mortality, all-cause mortality, and renal events were selected. Two reviewers screened abstracts and full papers of each study using standardized protocol.Results:We identified 31 studies fulfilling the criteria from 6546 abstracts. With regard to the risk of cardiovascular mortality, microalbuminuria (RR 1.76, 95%CI 1.38-2.25) and macroalbuminuria (RR 2.96 95%CI 2.44-3.60) were significant risk factors compared to normoalbuminuria. The same trends were seen in microalbuminuria (RR 1.60, 95%CI 1.42-1.81), and macroalbuminuria (RR 2.64, 95%CI 2.13-3.27) for the risk of all-cause mortality, and also in microalbuminuria (RR 3.21, 95%CI 2.05-5.02) and macroalbuminuria (RR 11.63, 95%CI 5.68-23.83) for the risk of renal events. The magnitudes of relative risks associated with low eGFR along with albuminuria were almost equal to multiplying each risk rate of low eGFR and albuminuria. No significant factors were found by investigating potential sources of heterogeneity using subgroup analysis.Conclusions:High albuminuria and low eGFR are relevant risk factors in diabetic patients. Albuminuria and low eGFR may be independent of each other. To evaluate the effects of low eGFR, intervention, or race, appropriately designed studies are needed. © 2013 Toyama et al.
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| 42.
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Popivanova, Boryana Konstantinova ; Kostadinova, Feodora Ivanova ; Furuichi, Kengo ; Shamekh, Mohamed M. ; Kondo, Toshikazu ; Wada, Takashi ; Egashira, Kensuke ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />Accumulating evidence indicates the crucial contribution of chronic inflammation to various types o
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f carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2-specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation. ©2009 American Association for Cancer Research.
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Komura, Takuya ; Sakai, Yoshio ; Harada, Kenichi ; Kawaguchi, Kazunori ; Takabatake, Hisashi ; Kitagawa, Hirohisa ; Wada, Takashi ; Honda, Masao ; Ohta, Tetsuo ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
Pancreatic ductal adenocarcinoma (PDAC) is among the most fatal of malignancies with an extremely poor prognosis. The ob
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jectives of this study were to provide a detailed understanding of PDAC pathophysiology in view of the host immune response. We examined the PDAC tissues, sera, and peripheral blood cells of PDAC patients using immunohistochemical staining, the measurement of cytokine/chemokine concentrations, gene expression analysis, and flow cytometry. The PDAC tissues were infiltrated by macrophages, especially CD33+CD163+ M2 macrophages and CD4+ T cells that concomitantly express programmed cell death-1 (PD-1). Concentrations of interleukin (IL)-6, IL-7, IL-15, monocyte chemotactic protein-1, and interferon-γ-inducible protein-1 in the sera of PDAC patients were significantly elevated. The gene expression profile of CD14+ monocytes and CD4+ T cells was discernible between PDAC patients and healthy volunteers, and the differentially expressed genes were related to activated inflammation. Intriguingly, PD-1 was significantly upregulated in the peripheral blood CD4+ T cells of PDAC patients. Correspondingly, the frequency of CD4+PD-1+ T cells was increased in the peripheral blood cells of PDAC patients, and this increase correlated to chemotherapy resistance. In conclusion, inflammatory conditions in both PDAC tissue and peripheral blood cells in PDAC patients were prominent, highlighting monocytes/macrophages as well as CD4+ T cells with influence of the clinical prognosis. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
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| 44.
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Ho, Tuyen Thuy Bich ; Nasti, Alessandro ; Seki, Akihiro ; Komura, Takuya ; Inui, Hiiro ; Kozaka, Takashi ; Kitamura, Yoji ; Shiba, Kazuhiro ; Yamashita, Taro ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Kawaguchi, Kazunori ; Wada, Takashi ; Honda, Masao ; Kaneko, Shuichi ; Sakai, Yoshio ; 関, 晃裕 ; 小村, 卓也 ; 小阪, 孝史 ; 北村, 暘二 ; 柴, 和弘 ; 山下, 太郎 ; 水腰, 英四郎 ; 川口, 和紀 ; 和田, 隆志 ; 本多, 政夫 ; 金子, 周一 ; 酒井, 佳夫
概要:
金沢大学疾患モデル総合研究センター<br />Background Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies,
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in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis. Methods The murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated. Results In the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages. Conclusion The combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells. ©
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| 45.
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和田, 隆志 ; Wada, Takashi
概要:
金沢大学医薬保健研究域医学系<br />慢性腎臓病では早期発見が重要である。そのため、軽微な腎障害の病態を反映し、その早期診断、治療反応性、予後を反映するバイオマーカー確立は慢性腎臓病の予後改善にむけて重要な課題である。本研究では、慢性腎臓
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病においてこのような病態を反映するアミノ酸の同定を行った。生体内のアミノ酸は光学異性体であるD体とL体が存在する。本研究では光学異性体のアミノ酸を区別し、かつ網羅的に解析可能なキラルアミノ酸メタボローム解析を用いた。その結果、慢性腎臓病の早期診断、予後などと関連するアミノ酸を同定した。腎生検によらない慢性腎臓病の非侵襲的診断、治療、予後を反映するバイオマーカーの確立に資する研究を施行し得た。<br />The number of patients suffering from chronic kidney disease (CKD), which is a risk factor for end-stage kidney disease resulting in requirement for renal replacement therapy is increasing all over the world. To overcome CKD, the establishment of adequate clinico-pathological parameters and related biomarkers for diagnosis and/or prediction for prognoses is required. Recent advances in research have shed light on the chirality of amino acids. The two-dimensional (2D) HPLC technique reveals that free D-amino acids and their L-forms are quantified quantitatively. In this study, we aimed to examine the pathophysiology of kidney diseases depending on amino acids and related relevant biomarker candidates for chronic kidney disease. As a result, we determined biomarker candidates, which were associated with the progression of chronic kidney disease.<br />研究課題/領域番号:16K15326, 研究期間(年度):2016-04-01 - 2018-03-31
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| 46.
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和田, 隆志 ; Wada, Takashi
概要:
糖尿病性腎症は透析導入原疾患の第1位である。さらに、超高齢社会を背景とした新規透析導入ならびに既存の腎臓病に対する影響も増加している。本研究の目的は、透析患者、高齢者が増加しているアジア、オセアニア地域における高齢糖尿病性腎症、腎硬化症の予
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後調査、予後関連因子の解析、バイオマーカー評価、本邦との国際比較を行うことである。アジア人種における糖尿病性腎症、腎硬化症の腎予後、心血管イベントならびに生命予後とそれらの予後関連因子の解析を共同で行った。予後検討に向けて、本邦の糖尿病性腎症の臨床、病理学的評価法による予後評価を用いて、国際的にアジア系人種のコホート間で比較、検証を行った。<br />This study was aimed to compare clinical outcomes and their related risk factors in patients with diabetic nephropathy and nephrosclerosis in Asian and Oceanian countries to our Japanese database. We have established international collaborative research team among Asian and Oceanian countries. International comparison of our results with Asian and Oceanian cohorts revealed that the presence of albuminuria and characteristic lesions in diseased kidneys was of importance for kidney prognosis. In addition, we have compared the prediction of prognosis using a novel biomarker candidate. In addition, prognostic risk factors from our Japanese database were closely relevant to those of Asian and Oceanian diabetic nephropathy patients. Taken together, these results suggested that the characteristic pathological lesions as well as the presence of albuminuria were clinically important to the long-term outcomes among Asian and Oceanian countries including Japan.<br />研究課題/領域番号:16H05837, 研究期間(年度):2016-04-01 - 2019-03-31
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| 47.
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和田, 隆志 ; Wada, Takashi
概要:
金沢大学医薬保健研究域医学系<br />本研究では、エリスロポエチン(EPO)とその受容体EPORを介する臓器合併症、ことに腎症の機序解明を目指し、糖尿病臓器合併症の共通進展機序である炎症、線維化に着目した。ヒト培養血管内皮細胞を用いて高糖
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,EPO投与有無による網羅解析とそこから得られる特異的応答分子機構を検討した。新規パスウェイとしてthioredoxin interacting proteinなどインフラマゾーム活性化につながる経路を同定した。一方、EPO投与により炎症、線維化シグナル、サイトカイン発現の低下を確認した。これらより、EPOはその受容体を介して、炎症、線維化カスケードの制御を行い病態に影響を与えている可能性がある。<br />Diabetic nephropathy is a leading cause of end-stage kidney disease requiring renal replacement therapy in the world. Therefore, it is of importance to examine the pathogenesis of progressive organ involvement in diabetic condition. Thus far, the presence of anemia is an independent risk factor for the progression of diabetic nephropathy. In this study, we focused on the role of erythropoietin (EPO) and its receptor (EPOR), which are closely related to anemia in kidney diseases, especially in the inflammatory processes during the progression of diabetic nephropathy. Endothelial cells express inflammatory and fibrotic mediators through the activation of inflammasome in response to high glucose conditions, which could be modulated by the presence of EPO. These results suggest that EPO-EPOR axis may play a role in the pathogenesis of diabetic nephropathy.<br />研究課題/領域番号:26293127, 研究期間(年度):2014-04-01 - 2017-03-31
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| 48.
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和田, 隆志 ; Wada, Takashi
概要:
金沢大学医薬保健研究域医学系<br />腎臓病において、蛋白尿は腎予後、生命予後と関連する。本研究の目的は、オミクス技術を用いてネフローゼ症候群における糸球体透過性因子の探索を行うことである。これまで、白血球除去療法(LCAP)が有効であっ
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たネフローゼ症候群の蛋白尿と相関性の高い因子をプロテオーム解析により抽出した。その結果、寛解時に比して発症時、再燃時において３倍以上発現した4因子が抽出された。このうち、1因子はLCAPで低下した。一方、寛解時に比較して発症時、再燃時において0.5倍以下に低下する9因子が抽出された。このうち、LCAPにより、4因子の相対的発現量が増加した。これらは蛋白尿に関連する糸球体透過性因子の可能性がある。<br />This study was aimed to determine circulating permeability factors possibly related to proteinuria in patients with nephrotic syndrome. Permeability factors derived from circulating T and/or B cells are speculated to have a crucial role in the proteinuria of nephrotic syndrome. Circulating factors in patients with beneficial effects of reducing proteinuria by removing lymphocytes treated with lymphocytapheresis were examined using proteomic studies and bioinformatics analyses. There were several circulating factors related to the onset and relapse of nephrotic syndrome. In contrast, other circulating factors could be detected when patients achieved remission. These factors might be involved in the pathogenesis of proteinuria in patients with nephrotic syndrome.<br />研究課題/領域番号:25670269, 研究期間(年度):2013-04-01 - 2015-03-31
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| 49.
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和田, 隆志 ; Wada, Takashi
概要:
金沢大学医薬保健研究域医学系<br />アジアの糖尿病性腎症の予後調査、予後関連因子解析、国際比較を目的とした。本邦の糖尿病性腎症の予後関連因子、予後判定のためのスコアリングを確立した（Wada, et al. Clin Exp Nephr
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ol 2014）。これを用いて、アジアコホート間で比較調査を行った。日本腎臓学会、Asian Forum of CKD Initiativeと連携し、糖尿病性腎症のアジア共同研究体制を構築した。台湾2大学のコホートで予後評価を行った。予後関連因子としてのアルブミン尿の重要性、本邦の予後推定スコアリングの有効性を示した。アジアの他コホートを用いた国際調査も進行している。<br />This study was aimed to compare outcomes and their related risk factors in patients with diabetic nephropathy among Asian countries based on our Japanese database in patients with diabetic nephropathy. Our study strongly showed that the presence of macroalbuminuria increased the adjusted hazard ratios for kidney event (Wada, et al. Clin Exp Nephrol 2014). Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for kidney event, cardiovascular events and death. Then, we have established international collaborative research team on diabetic nephropathy among Asian countries. The results of advanced diabetic patients from Taiwanese diabetic cohorts confirmed that albuminuria was of importance for kidney prognosis. In addition, these showed that related prognostic risk factors from our Japanese database were closely relevant to those of Asian diabetic nephropathy patients.<br />研究課題/領域番号:24406028, 研究期間(年度):2012-04-01 - 2015-03-31
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和田, 隆志 ; Wada, Takashi
概要:
CD45/I型コラーゲン二重陽性細胞に着目し、腎間質線維化ならびに心線維化を中心とした心腎連関への関与を検討した。この線維化を基盤とする心腎連関モデルの作成により、CD45/I型コラーゲン二重陽性細胞の心ならびに腎の線維化への関与が示唆され
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た。また、臨床的に線維化を反映する臨床検査診断法の確立への期待は強い。今回、CD45/I型コラーゲン二重陽性細胞の測定系が樹立され、今後、臨床上の有用性を検討していきたい。<br />CD45^<+/>Collagen I^+ dual positive cells migrate into fibrotic kidney dependent on chemokine system, which may promote and escalate chronic inflammatory processes and possible interaction with resident stromal cells, thereby perpetuating renal fibrosis. In addition, our present data suggest the possible involvement of CD45^+/Collagen I^+ dual positive cells in cardiac fibrosis, closely related to renal lesions. Furthermore, the detection of CD45^+/Collagen I^+ dual positive cells in circulation has been established in this study.
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| 51.
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和田, 隆志 ; Wada, Takashi
概要:
腎線維化は進行性腎臓病の共通進展経路であり、その機序解明と治療戦略構築は重要な課題である。本研究において、新規の骨髄由来白血球系細胞、fibrocyteに着目し腎線維化における関与を検討した。1)fibrocyteの腎間質線維化機序への関与
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とその治療標的としての可能性:腎線維化におけるfibrocyteの意義をマウス一側尿管結紮モデル(UUO)を用いて検討した。CD45/I型コラーゲン共陽性fibrocyteは皮髄境界領域を中心に浸潤し線維化進展に伴い増加した。CCL21/CCR7阻害にて,CD45/I型コラーゲン二重陽性fibrocyte浸潤の減少とともに間質線維化の改善を認めた。2)各種ヒト腎臓病例におけるfibrocyteの意義:各種腎臓病115例において、fibrocyteは間質を中心に浸潤し、腎機能と負相関、線維化と正相関した。3)腎線維化におけるレニン・アンジオテンシン系(RAS)とfibrocyteの関連:UUOにおいて、浸潤fibrocyte数、腎線維化面積、腎内Co1ImRNA発現はangiotensinII(AII)受容体type2欠損マウス(AT2k/o)において対照マウスに比し高値であり、AT1阻害薬投与でいずれも減少した。骨髄中のfibrocytes数は、AT2k/oにおいて対照に比し高値であり、AT1阻害薬投与投与でいずれも減少した。(まとめ)fibrocyteはCCL21/CCR7シグナリングによる腎浸潤および活性化を介して腎線維化に関与する。さらにRASは骨髄・腎におけるfibrocyte増殖・活性化調節を介して腎線維化に関与することが示唆された。RAS阻害薬の腎はじめ臓器線維化抑制効果の少なくとも一部は、fibrocyteの制御を介している可能性が示された。<br />Fibrocytes are supposed to be a circulating connective tissue cell progenitor that consists of a novel population of peripheral blood cells. This distinct population of blood-borne cells shares markers of leukocytes as well as mesenchymal cells. Accumulating evidence indicates that fibrosis is characteristic of progressive chronic kidney diseases of any etiologies, resulting in kidney failure. We have uncovered that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to kidney fibrosis induced by unilateral ureteral obstruction in mice. In addition, the blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced kidney fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in macrophage recruitment along with reduced renal transcripts of monocyte chemoattractant protein-1 (MCP-1/CCL2). In addition, angiotensin receptor type 1 /type 2 signaling may contribute to the pathogenesis of renal fibrosis by at least two mechanisms: (1) by regulating the number of fibrocytes in bone marrow, and (2) by direct activation of fibrocytes via these two receptors. These findings suggest that fibrocytes dependent on CCL21/CCR7 signaling pathways and renin-angiotensin system contribute to the pathogenesis of kidney fibrosis, thereby providing that regulating fibrocytes may provide a novel therapeutic benefit for kidney fibrosis.<br />研究課題/領域番号:18590887, 研究期間(年度):2006-2007<br />出典：「骨髄由来細胞を介した新規の腎線維化機序の解析」研究成果報告書 課題番号18590887 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 52.
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和田, 隆志 ; Wada, Takashi
概要:
Interferon-inducible protein-10(IP-10)/CXCL10およびその受容体CXCR3の腎発生ならびに腎進行性線維化への関与を検討した1)IP-10ならびCXCR3はマウス胎児期において腎組織内に発現がみられる
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ことが判明した.一旦,マウス腎が成熟する生後1週以降ではほとんど発現がみられなくなった.一方,虚血再環流障害モデルを作成したところ,IP-10ならびにCXCR3ともに間質浸潤細胞ならびに尿細管上皮細胞に発現を認めた.この新たに発現がみられるIP-10/CXCR3の役割を検討する目的で,虚血再環流障害モデル作成時に抗IP-10中和抗体投与を行った.その結果,抗IP-10中和抗体投与群において,対照群と比較して再環流後4日で尿細管上皮細胞の再生が増加することが判明した.さらにこの虚血再環流モデルにおいて,尿細管上皮細胞増殖の亢進がKi67陽性細胞数増加より示された.さらに培養マウス尿細管上皮細胞を用いてwound healing testを施行した.その結果,抗IP-10中和抗体投与によりwound healingが促進することが示された.さらに,抗IP-10中和抗体共培養によりKi67陽性細胞で示される細胞増殖が促進された.2)進行性腎線維化モデルにおける意義を検討した.抗IP-10中和抗体投与群において4日,7日目に腎間質線維化率の増加を確認した.さらに組織コラーゲン含有をあらわすハイドロキシプロリン量も増加した.加えて,TGF-β_1蛋白ならびにmRNAの腎での発現は増加した.この発現は,抗IP-10中和抗体投与によりさらに亢進した.一方,線維化抑制効果を示すと考えられているHGF mRNA発現も同様に増加した.抗IP-10中和抗体はこのHGF mRNA発現を抑制した.培養マウス尿細管上皮細胞においてH_2O_2存在下のTGF-β_1 mRNA発現はリコンビナントIP-10添加により減少し,抗IP-10中和抗体により増加した.以上の結果より,抗IP-10中和抗体投与により腎線維化促進効果がみられ,この機序として尿細管上皮細胞でのTGFβ_1発現亢進ならびにHGF発現低下を介していることが推測された.以上より,IP-10/CXCR3は腎発生ならびに腎線維化に至る修復機構に深く関与する因子であることが推測される.<br />Studies of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in various inflammatory diseases including renal ones. Chemokine receptors expressed on renal resident cells might be involved in proliferation, proteinuria and fibrogenesis. Novel biological functions of chemokines would expand their universe beyond chemotaxis and activation of inflammatory cells in renal diseases. Importantly, IP-10 and its cognate receptor CXCR3 are now considered to contribute to renal development. In addition, IP-10/CXCR3 play a role in progressive renal fibrosis, which is a hallmark of progressive renal diseases despite their etiologies. The selective intervention of IP-10/CXCR3 via the administration of anti-IP-10 neutralizing antibodies enhanced progressive renal fibrosis. This IP-10-CXCR3-dependent anti-fibrotic mechanism(s) was confirmed in CXCR3 gene targeted mice. These findings suggest that IP-10/CXCR3 may prove beneficial for progressive renal fibrosis.<br />研究課題/領域番号:16590784, 研究期間(年度):2004-2005<br />出典：「ケモカインを介した腎発生ならびに再静機序とその制御」研究成果報告書 課題番号16590784 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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論文
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和田, 隆志 ; Wada, Takashi
概要:
細胞の遊走・活性化能を有するケモカインmonocyte chemoattractant protin-1 (MCP-1)/CCL2およびその受容体CCR2に焦点をあて,進行性腎間質線維化機構化への関与ならびに治療標的分子としての可能性につい
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て検討した.(1)MCP-1/CCR2のヒト間質線維化への関与ヒト炎症性腎疾患,糖尿病性腎症ならびに膜性腎症例においてMCP-1/CCR2は主として間質に陽性であった.尿中MCP-1値は尿細管萎縮,間質線維化ならびに浸潤マクロファージと正の相関を示し,進行性間質病変にはたすMCP-1の関与が推測された.このことからMCP-1/CCR2は病因を問わず尿細管間質障害に病態特異的に関与し,共通の進展因子である可能性が示された.これはMCP-1/CCR2が標的分子として治療戦略上重要であることを示唆する.(2)MCP-1/CCR2を治療標的分子とした間質線維化治療の基礎的検討コントロールマウスに一側尿管結紮術モデルを作成し4,7,14日目にと殺した結果,進行性の間質線維化に加えて,尿細管萎縮ならびにF4/80陽性マクロファージ浸潤が確認された.この過程において,間質内I型コラーゲンはタンパクならびにmRNA発現がいずれも亢進していた.加えて線維化に関与するTGF-β発現も亢進していた.7NDによる遺伝子治療,CCR2欠損マウスならびにpropagermanium投与によりMCP-1/CCR2のシグナル伝達を阻害した.その結果,進行性間質線維化の改善とともに,I型コラーゲン,TGF-β発現は低下した.さらにF4/80陽性マクロファージを主体とする間質内細胞浸潤はいずれのMCP-1/CCR2阻害においても有意に抑制された.さらに主として間質に発現が増強するMCP-1は,MCP-1/CCR2抑制によりその発現が減少した.以上,腎間質線維化に至る尿細管・間質障害の進展過程において,腎疾患の病因を問わない共通進展因子としてのMCP-1/CCR2の意義ならびに治療標的分子としての可能性が示された.<br />Studies of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in various inflammatory diseases including renal ones.Chemokine receptors expressed on renal resident cells might be involved in proliferation, proteinuria and fibrogenesis.Novel biological functions of chemokines would expand their universe beyond chemotaxis and activation of inflammatory cells in renal diseases. Importantly, MCP-1 and its cognate receptor CCR2 are now considered to contribute to progressive renal fibrosis, which is a hallmark of progressive renal diseases despite their etiologies, including diabetic nephropathy.The selective intervention of MCP-1-CCR2 via the administration of anti-MCP-1 neutralizing antibodies, CCR2 antagonists and the MCP-1 mutant ameliorated progressive renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-p. This MCP-1-CCR2-dependent loop for progressive renal fibrosis was confirmed in CCR2 gene targeted mice.These findings suggest that the therapeutic strategy of blocking MCP-1-CCR2 may prove beneficial for progressive renal fibrosis.<br />研究課題/領域番号:14571019, 研究期間(年度):2002-2003<br />出典：「ケモカイン受容体を介した腎間質線維化機構とその制御」研究成果報告書 課題番号14571019(KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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