Faculty Profiles - MIZUNO, Masashi

Apoptosis inhibitor of macrophage ameliorates fungus-induced peritoneal injury model in mice Reviewed International journal

Takako Tomita, Satoko Arai, Kento Kitada, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Daisuke Nakano, Emiri Hiramoto, Yoshifumi Takei, Shoichi Maruyama, Akira Nishiyama, Seiichi Matsuo, Toru Miyazaki, Yasuhiko Ito

SCIENTIFIC REPORTS Vol. 7 ( 1 ) page： 6450 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Fungal peritonitis in a patient on peritoneal dialysis (PD) is a refractory injury accompanied by severe inflammation, predisposing patients to a poor prognosis. Defective clearance of necrotic tissue interferes with amelioration of tissue injury and induces abnormal tissue remodeling. In the recent reports, apoptosis inhibitor of macrophage (AIM, also called CD5L) prevents obesity, hepatocellular carcinoma and acute kidney injury. Here, we investigated potential roles of AIM in prevention of progression of fungal peritonitis models. AIM(-/)-mice subjected to zymosan-induced peritonitis exhibited progressive inflammation and sustained peritoneal necrosis tissue on day 28 after the disease induction, whereas there was an improvement in AIM(+/+) mice. This appeared to be caused by deposition of AIM at the necrotic peritoneum in AIM(+/+) mice. In vitro, AIM enhanced the engulfment of necrotic debris by macrophages derived from zymosan-induced peritonitis, M1-and M2a-like bone marrow derived macrophages, as well as by mesothelial cells. In addition, administration of recombinant AIM dramatically ameliorated severe inflammation associated with necrosis in zymosan-induced peritonitis of AIM(-/)-mice. Our observations suggest that AIM appears to be involved in the repair process of zymosan-induced peritonitis, and thus, could be the basis of development of new therapeutic strategies for PD-related fungal peritonitis.

DOI： 10.1038/s41598-017-06824-6

Sodium chloride promotes tissue inflammation via osmotic stimuli in subtotal-nephrectomized mice Reviewed International coauthorship International journal

Fumiko Sakata, Yasuhiko Ito, Masashi Mizuno, Akiho Sawai, Yasuhiro Suzuki, Takako Tomita, Mitsuhiro Tawada, Akio Tanaka, Akiyoshi Hirayama, Akihiro Sagara, Takashi Wada, Shoichi Maruyama, Tomoyoshi Soga, Seiichi Matsuo, Enyu Imai, Yoshifumi Takei

LABORATORY INVESTIGATION Vol. 97 ( 4 ) page： 432 - 446 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Chronic inflammation, which is often associated with high all-cause and cardiovascular mortality, is prevalent in patients with renal failure; however, the precise mechanisms remain unclear. High-salt intake was reported to induce lymphangiogenesis and autoimmune diseases via osmotic stimuli with accumulation of sodium or chloride. In addition, sodium was recently reported to be stored in the extremities of dialysis patients. We studied the effects and mechanisms of high salt loading on tissue and systemic inflammation in subtotal-nephrectomized mice (5/6Nx) and in cultured cells. Macrophage infiltration in the peritoneal wall (P<0.001), heart (P<0.05) and para-aortic tissues (P<0.001) was significantly higher in 5/6Nx with salt loading (5/6Nx/NaCl) than in 5/6Nx without salt loading (5/6Nx/Water); however, there were no significant differences in blood pressure and renal function between the groups. Tissue interleukin-6, monocyte chemotactic protein-1 (MCP-1), serum- and glucocorticoid-inducible kinase 1 (Sgk1) and tonicity-responsive enhancer binding protein (TonEBP) mRNA were significantly elevated in the peritoneal wall and heart with 5/6Nx/NaCl when compared with 5/6Nx/Water. Sodium was stored in the abdominal wall, exerting high-osmotic conditions. Reversal of salt loading reduced macrophage infiltration associated with decreased TonEBP in 5/6Nx/NaCl. Macrophage infiltration associated with fibrosis induced by salt loading was decreased in the 5/6Nx/NaCl/CC chemokine receptor 2 (CCR2, receptor of MCP-1)-deficient mice when compared with 5/6Nx/NaCl/Wild mice, suggesting that CCR2 is required for macrophage infiltration in 5/6Nx with NaCl loading. In cultured mesothelial cells and cardiomyocytes, culture media with high NaCl concentration induced MCP-1, Sgk1 and TonEBP mRNA, all of which were suppressed by TonEBP siRNA, indicating that both MCP-1 and Sgk1 are downstream of TonEBP. Our study indicates that high NaCl intake induces MCP-1 expression leading to macrophage infiltration via the TonEBP-MCP-1 pathway in 5/6Nx/NaCl mice, and that TonEBP has a central role in inflammation in patients with renal failure taking high salt.

DOI： 10.1038/labinvest.2017.4

Therapeutic effects of a C5a antagonist, AcPepA, for severe peritoneal injuries associated with fungal infection in a rat model

Tetracycline Reduces Kidney Damage Induced by <i>Loxosceles</i> Spider Venom Reviewed International coauthorship International journal

Okamoto, CK; Van den Berg, CW; Masashi, M; Gonçalves-de-Andrade, RM; Tambourgi, DV

TOXINS Vol. 9 ( 3 ) 2017.3

Complement component 5 promotes lethal thrombosis International journal

Mizuno Tomohiro, Yoshioka Kengo, Mizuno Masashi, Shimizu Mie, Nagano Fumihiko, Okuda Tomoyuki, Tsuboi Naotake, Maruyama Shoichi, Nagamatsu Tadashi, Imai Masaki

SCIENTIFIC REPORTS Vol. 7 page： 42714 2017.2

PDのエビデンス

多和田光洋, 鈴木康弘, 水野正司, 伊藤恭彦

日本透析医学会雑誌 Vol. 50 ( 11 ) page： 685 - 691 2017

Masashi Mizuno, Daiki Iguchi, Emi Shigemoto, Kazuma Kobayashi, Fumiko Sakata, Yasuhiro Suzuki, Alan Okada, Hidechika Okada, Seiichi Matsuo, Yasuhiko Ito

IMMUNOBIOLOGY Vol. 221 ( 10 ) page： 1212 - 1212 2016.10

C5 promotes histone-induced lethal thromboembolism Reviewed

Tomohiro Mizuno, Kengo Yoshioka, Masashi Mizuno, Naotake Tsuboi, Shoichi Maruyama, Tadashi Nagamatsu, Masaki Imai

IMMUNOBIOLOGY Vol. 221 ( 10 ) page： 1140 - 1141 2016.10

Complement promote releasing transglutaminase 2 from cytoplasm Reviewed International journal

Hara Kaori, Mizuno Tomohiro, Takahashi Kazuo, Mizuno Masashi, Kato Akihiro, Onouchi Takanori, Tsutsumi Yutaka, Tatsukawa Hideki, Nagamatsu Tadashi, Hitomi Kiyotaka, Yuzawa Yukio

IMMUNOBIOLOGY Vol. 221 ( 10 ) page： 1142 - 1142 2016.10

TGF-beta-VEGF-A PATHWAY INDUCES NEOANGIOGENESIS IN PERITONEAL FIBROSIS OF PERITONEAL DIALYSIS

Tetsuyoshi Kariya, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Takeshi Terabayashi, Takako Ishii, Mitsuhiro Tawada, Daiki Iguchi, Shoichi Maruyama, Seiichi Matsuo

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 31 page： 35 - 35 2016.5

APOPTOSIS INHIBITOR OF MACROPHAGE PROTEIN AMELIORATES FUNGUS-INDUCED PERITONEAL INJURY IN MICE BY UPREGULATION OF CLEARANCE OF NECROTIC DEBRIS

Takako Tomita, Yasuhiko Ito, Kento Kitada, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Daisuke Nakano, Shoichi Maruyama, Satoko Arai, Toru Miyazaki, Akira Nishiyama, Seiichi Matsuo

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 31 page： 1503 - 1503 2016.5

Vascular Endothelial Cell Injury Is an Important Factor in the Development of Encapsulating Peritoneal Sclerosis in Long-Term Peritoneal Dialysis Patients. Reviewed International journal

Tawada M, Ito Y, Hamada C, Honda K, Mizuno M, Suzuki Y, Sakata F, Terabayashi T, Matsukawa Y, Maruyama S, Imai E, Matsuo S, Takei Y

PloS one Vol. 11 ( 4 ) page： e0154644 2016.4

Depression of complement regulatory factors in rat and human renal grafts is associated with the pregress of acute T-cell medicated rejection. Reviewed

Yamanaka K., Kakuta Y., Miyagawa S., Nakazawa S., Kato T., Abe T., Imamura R., Okumi M., Maeda A., Mizuno M., Nonomura N.

PlosOne Vol. 11 ( 2 ) page： e0148881 2016

Rat Models of Acute and/or Chronic Peritoneal Injuries Including Peritoneal Fibrosis and Peritoneal Dialysis Complications

Mizuno Masashi, Ito Yasuhiko

KIDNEY RESEARCH: EXPERIMENTAL PROTOCOLS, 2ND EDITION Vol. 1397 page： 35 - 43 2016

Increase of Antimyeloperoxidase Antineutrophil Cytoplasmic Antibody (ANCA) in Patients with Renal ANCA-associated Vasculitis: Association with Risk to Relapse. Reviewed International journal

Yamaguchi M, Ando M, Kato S, Katsuno T, Kato N, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S

The Journal of rheumatology Vol. 42 ( 10 ) page： 1853 - 1860 2015.10

Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury Reviewed International journal

Takeshi Terabayashi, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Hiroshi Kinashi, Fumiko Sakata, Takako Tomita, Daiki Iguchi, Mitsuhiro Tawada, Ryosuke Nishio, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo, Yoshifumi Takei

LABORATORY INVESTIGATION Vol. 95 ( 9 ) page： 1029 - 1043 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-beta 1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P<0.05) and day 50 after reduction of inflammation (P<0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P<0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.

DOI： 10.1038/labinvest.2015.87