Updated on 2024/03/19
Doctor(Medicine) （ 2006.3 Nagoya University ）
Nagoya University Graduate School, Division of Medical Sciences
2002.4 - 2006.3
Country： Japan
Hirosaki University Faculty of Medicine
1989.4 - 1995.3
Country： Japan
日本内科学会
日本腎臓学会
American Society of Nephrology
日本透析学会
日本免疫学会
日本糖尿病学会
Detecting and exploring kidney-derived extracellular vesicles in plasma
Komatsu, S; Kato, N; Kitai, H; Funahashi, Y; Noda, Y; Tsubota, S; Tanaka, A; Sato, Y; Maeda, K; Saito, S; Furuhashi, K; Ishimoto, T; Kosugi, T; Maruyama, S; Kadomatsu, K
CLINICAL AND EXPERIMENTAL NEPHROLOGY 2024.3
Tanaka, A; Watanabe, Y; Furuhashi, K; Saito, S; Yasuda, Y; Kosugi, T; Sano, Y; Kato, M; Maruyama, S
THERAPEUTIC APHERESIS AND DIALYSIS Vol. 28 ( 1 ) page： 152 - 157 2024.2
Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study
Kurasawa, S; Kato, S; Ozeki, T; Akiyama, S; Ishimoto, T; Mizuno, M; Tsuboi, N; Kato, N; Kosugi, T; Maruyama, S
CLINICAL AND EXPERIMENTAL NEPHROLOGY 2024.1
Watanabe, T; Maeda, K; Kato, N; Seko, H; Sugimura, M; Sato, Y; Ryuge, A; Kato, S; Kadomatsu, K; Maruyama, S; Kosugi, T
NEPHROLOGY Vol. 28 ( 11 ) page： 629 - 638 2023.11
Goto, K; Imaizumi, T; Hamada, R; Ishikura, K; Kosugi, T; Narita, I; Sugiyama, H; Shimizu, A; Yokoyama, H; Sato, H; Mauryama, S
JOURNAL OF NEPHROLOGY Vol. 36 ( 8 ) page： 2257 - 2267 2023.11
Fructose might be a clue to the origin of preeclampsia insights from nature and evolution
Nakagawa Takahiko, Andres-Hernando Ana, Kosugi Tomoki G., Sanchez-Lozada Laura, Stenvinkel Peter, Kublickiene Karolina, Karumanchi S. Ananth, Kang Duk-Hee, Kojima Hideto, Rodriguez-Iturbe Bernardo R., Tolan Dean A., Lanaspa Miguel J., Johnson Richard
HYPERTENSION RESEARCH Vol. 46 ( 3 ) page： 646 - 653 2023.3
IgA-dominant glomerulonephritis with DNAJB9-negative fibrillar polytypic immunoglobulin deposits in the subepithelium
Muto Reiko, Maeda Kayaho, Fukui Sosuke, Saito Shoji, Kato Noritoshi, Kosugi Tomoki, Shimizu Akira, Maruyama Shoichi
CEN CASE REPORTS 2022.12
Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis
Kitai Hiroki, Kato Noritoshi, Ogami Koichi, Komatsu Shintaro, Watanabe Yu, Yoshino Seiko, Koshi Eri, Tsubota Shoma, Funahashi Yoshio, Maeda Takahiro, Furuhashi Kazuhiro, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Kadomatsu Kenji, Suzuki Hiroshi I
BMC BIOLOGY Vol. 20 ( 1 ) page： 248 2022.11
Increased Monocyte/Lymphocyte Ratio as Risk Marker for Cardiovascular Events and Infectious Disease Hospitalization in Dialysis Patients
Muto Reiko, Kato Sawako, Lindholm Bengt, Qureshi Abdul Rashid, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi
BLOOD PURIFICATION Vol. 51 ( 9 ) page： 747 - 755 2022.9
Protocol for a Phase 1, Open-Label, Multiple-Center, Dose-Escalation Study to Evaluate the Safety and Tolerability of ADR-001 in the Treatment of Immunoglobulin A Nephropathy
Tanaka Akihito, Furuhashi Kazuhiro, Fujieda Kumiko, Maeda Kayaho, Saito Shoji, Mimura Tetsushi, Saka Yosuke, Naruse Tomohiko, Ishimoto Takuji, Kosugi Tomoki, Kinoshita Fumie, Kuwatsuka Yachiyo, Shimizu Shinobu, Nakai Yasuhiro, Maruyama Shoichi
FRONTIERS IN MEDICINE Vol. 9 page： 883168 2022.5
Sex differences in clinical outcomes in Japanese incident dialysis patients: a prospective observational multicenter study
Kozaki Yohei, Morinaga Takatoshi, Fukatsu Atsushi, Ito Takeshi, Ishimoto Takuji, Kosugi Tomoki, Inaguma Daijo, Tamai Hirofumi, Maruyama Shoichi
CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 26 ( 5 ) page： 466 - 475 2022.5
Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis
Ryuge Akihiro, Kosugi Tomoki, Maeda Kayaho, Banno Ryoichi, Gou Yang, Zaitsu Kei, Ito Takanori, Sato Yuka, Hirayama Akiyoshi, Tsubota Shoma, Honda Takashi, Nakajima Kazuki, Ozaki Tomoya, Kondoh Kunio, Takahashi Kazuo, Kato Noritoshi, Ishimoto Takuji, Soga Tomoyoshi, Nakagawa Takahiko, Koike Teruhiko, Arima Hiroshi, Yuzawa Yukio, Minokoshi Yasuhiko, Maruyama Shoichi, Kadomatsu Kenji
JCI INSIGHT Vol. 6 ( 20 ) 2021.10
Efficacy of favipiravir for an end stage renal disease patient on maintenance hemodialysis infected with novel coronavirus disease 2019
Koshi Eri, Saito Shoji, Okazaki Masaki, Toyama Yuki, Ishimoto Takuji, Kosugi Tomoki, Hiraiwa Hiroaki, Jingushi Naruhiro, Yamamoto Takanori, Ozaki Masayuki, Goto Yukari, Numaguchi Atsushi, Miyagawa Yasuhiro, Kato Io, Tetsuka Nobuyuki, Yagi Tetsuya, Maruyama Shoichi
CEN CASE REPORTS Vol. 10 ( 1 ) page： 126 - 131 2021.2
The ISN/RPS 2016 classification predicts renal prognosis in patients with first-onset class III/IV lupus nephritis
Hachiya Asaka, Karasawa Munetoshi, Imaizumi Takahiro, Kato Noritoshi, Katsuno Takayuki, Ishimoto Takuji, Kosugi Tomoki, Tsuboi Naotake, Maruyama Shoichi
SCIENTIFIC REPORTS Vol. 11 ( 1 ) page： 1525 2021.1
Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis
Ryuge Akihiro, Kim Hangsoo, Suzuki Yasuhiro, Okazaki Masaki, Kojima Hiroshi, Saito Shoji, Kato Noritoshi, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Mizuno Masashi
INTERNAL MEDICINE Vol. 60 ( 15 ) page： 2461 - 2464 2021
Acquired Fanconi Syndrome in a Patient with Nontyphoidal Salmonella Bacteremia
Ryuge Akihiro, Saito Shoji, Morioka Hiroshi, Hachiya Asaka, Kato Noritoshi, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi
INTERNAL MEDICINE Vol. 60 ( 5 ) page： 761 - 764 2021
A Prospective, Randomized Clinical Trial of Etelcalcetide in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism (the DUET Trial)
Itano Yuya, Kato Sawako, Tsuboi Masato, Kasuga Hirotake, Tsuruta Yoshinari, Sato Fumihiko, Hishida Manabu, Ishimoto Takuji, Kosugi Tomoki, Ando Masahiko, Kuwatsuka Yachiyo, Maruyama Shoichi
KIDNEY INTERNATIONAL REPORTS Vol. 5 ( 12 ) page： 2168 - 2177 2020.12
ANALYSIS OF FREQUENCY AND KINDS OF ALARM HISTORIES OF HOME PD SYSTEM KAGUYA DURING THE INTRODUCTION: PERIOD IN A SINGLE CENTRE
Hiramatsu Tetsuaki, Mizuno Masasi, Suzuki Yasuhiro, Nomori Sumiyo, Suzuki Masafumi, Shiga Yoshiko, Sato Yuka, Nakamura Tomohiro, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Koyama Tomio
NEPHROLOGY Vol. 25 page： 77 - 78 2020.10
Guideline on the use of iodinated contrast media in patients with kidney disease 2018
Isaka Yoshitaka, Hayashi Hiromitsu, Aonuma Kazutaka, Horio Masaru, Terada Yoshio, Doi Kent, Fujigaki Yoshihide, Yasuda Hideo, Sato Taichi, Fujikura Tomoyuki, Kuwatsuru Ryohei, Toei Hiroshi, Murakami Ryusuke, Saito Yoshihiko, Hirayama Atsushi, Murohara Toyoaki, Sato Akira, Ishii Hideki, Takayama Tadateru, Watanabe Makoto, Awai Kazuo, Oda Seitaro, Murakami Takamichi, Yagyu Yukinobu, Joki Nobuhiko, Komatsu Yasuhiro, Miyauchi Takamasa, Ito Yugo, Miyazawa Ryo, Kanno Yoshihiko, Ogawa Tomonari, Hayashi Hiroki, Koshi Eri, Kosugi Tomoki, Yasuda Yoshinari, Isaka Yoshitaka, Horio Masaru, Terada Yoshio, Doi Kent, Fujigaki Yoshihide, Yasuda Hideo, Sato Taichi, Fujikura Tomoyuki, Joki Nobuhiko, Komatsu Yasuhiro, Miyauchi Takamasa, Ito Yugo, Kanno Yoshihiko, Ogawa Tomonari, Hayashi Hiroki, Koshi Eri, Kosugi Tomoki, Yasuda Yoshinari, Hayashi Hiromitsu, Kuwatsuru Ryohei, Toei Hiroshi, Murakami Ryusuke, Awai Kazuo, Oda Seitaro, Murakami Takamichi, Yagyu Yukinobu, Miyazawa Ryo, Aonuma Kazutaka, Saito Yoshihiko, Watanabe Makoto, Hirayama Atsushi, Murohara Toyoaki, Sato Akira, Ishii Hideki, Takayama Tadateru
CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 24 ( 1 ) page： 1 - 44 2020.1
Guideline on the use of iodinated contrast media in patients with kidney disease 2018
Isaka Yoshitaka, Hayashi Hiromitsu, Aonuma Kazutaka, Horio Masaru, Terada Yoshio, Doi Kent, Fujigaki Yoshihide, Yasuda Hideo, Sato Taichi, Fujikura Tomoyuki, Kuwatsuru Ryohei, Toei Hiroshi, Murakami Ryusuke, Saito Yoshihiko, Hirayama Atsushi, Murohara Toyoaki, Sato Akira, Ishii Hideki, Takayama Tadateru, Watanabe Makoto, Awai Kazuo, Oda Seitaro, Murakami Takamichi, Yagyu Yukinobu, Joki Nobuhiko, Komatsu Yasuhiro, Miyauchi Takamasa, Ito Yugo, Miyazawa Ryo, Kanno Yoshihiko, Ogawa Tomonari, Hayashi Hiroki, Koshi Eri, Kosugi Tomoki, Yasuda Yoshinari, Miyauchi Takamasa, Ito Yugo, Kanno Yoshihiko, Ogawa Tomonari, Hayashi Hiroki, Koshi Eri
JAPANESE JOURNAL OF RADIOLOGY Vol. 38 ( 1 ) page： 3 - 46 2020.1
Successful Introduction of Peritoneal Dialysis in an End-stage Renal Failure Patient with Idiopathic Aplastic Anemia
Suzuki Yasuhiro, Mizuno Masashi, Sakata Fumiko, Kojima Hiroshi, Sato Yuka, Kishimoto Mayuko, Suzuki Nobuaki, Kinashi Hiroshi, Saito Shoji, Katsuno Takayuki, Kosugi Tomoki, Maruyama Shoichi, Murata Makoto, Kiyoi Hitoshi, Ito Yasuhiko
INTERNAL MEDICINE Vol. 59 ( 5 ) page： 683-687 2020
Guideline on the Use of Iodinated Contrast Media in Patients With Kidney Disease 2018
Isaka Yoshitaka, Hayashi Hiromitsu, Aonuma Kazutaka, Horio Masaru, Terada Yoshio, Doi Kent, Fujigaki Yoshihide, Yasuda Hideo, Sato Taichi, Fujikura Tomoyuki, Kuwatsuru Ryohei, Toei Hiroshi, Murakami Ryusuke, Saito Yoshihiko, Hirayama Atsushi, Murohara Toyoaki, Sato Akira, Ishii Hideki, Takayama Tadateru, Watanabe Makoto, Awai Kazuo, Oda Seitaro, Murakami Takamichi, Yagyu Yukinobu, Joki Nobuhiko, Komatsu Yasuhiro, Miyauchi Takamasa, Ito Yugo, Miyazawa Ryo, Kanno Yoshihiko, Ogawa Tomonari, Hayashi Hiroki, Koshi Eri, Kosugi Tomoki, Yasuda Yoshinari
CIRCULATION JOURNAL Vol. 83 ( 12 ) page： 2572 - 2607 2019.12
Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure
Sato Yuka, Roncal-Jimenez Carlos A., Andres-Hernando Ana, Jensen Thomas, Tolan Dean R., Sanchez-Lozada Laura G., Newman Lee S., Butler-Dawson Jaime, Sorensen Cecilia, Glaser Jason, Miyazaki Makoto, Diaz Henry F., Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Garcia Gabriela E., Lanaspa Miguel A., Johnson Richard J.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 317 ( 5 ) page： F1111-F1121 2019.11
Circulating levels of CD34+ cells predict long-term cardiovascular outcomes in patients on maintenance hemodialysis.
Kaihan AB, Hishida M, Imaizumi T, Okazaki M, Kaihan AN, Katsuno T, Taguchi A, Yasuda Y, Tsuboi N, Kosugi T, Maruyama S
PloS one Vol. 14 ( 10 ) page： e0223390 2019.10
Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase
Hayasaki Takahiro, Ishimoto Takuji, Doke Tomohito, Hirayama Akiyoshi, Soga Tomoyoshi, Furuhashi Kazuhiro, Kato Noritoshi, Kosugi Tomoki, Tsuboi Naotake, Lanaspa Miguel A., Johnson Richard J., Maruyama Shoichi, Kadomatsu Kenji
JOURNAL OF NUTRITIONAL BIOCHEMISTRY Vol. 71 page： 54-62 2019.9
The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial. Reviewed
Tsujita M, Kosugi T, Goto N, Futamura K, Nishihira M, Okada M, Hiramitsu T, Narumi S, Uchida K, Takeda A, Morozumi K, Maruyama S, Watarai Y.
Nephrol Dial Transplant. Vol. 34 ( 8 ) page： 1409 - 1416 2019.8
miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury. Reviewed
Funahashi Y, Kato N, Masuda T, Nishio F, Kitai H, Ishimoto T, Kosugi T, Tsuboi N, Matsuda N, Maruyama S, Kadomatsu K.
Lab Invest. Vol. 99 ( 8 ) page： 1130 - 1142 2019.8
CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling
Yoshioka Tomoki, Kosugi Tomoki, Masuda Tomohiro, Watanabe Tomoharu, Ryuge Akihiro, Nagaya Hiroshi, Maeda Kayaho, Sato Yuka, Katsuno Takayuki, Kato Noritoshi, Ishimoto Takuji, Yuzawa Yukio, Maruyama Shoichi, Kadomatsu Kenji
AMERICAN JOURNAL OF PATHOLOGY Vol. 189 ( 7 ) page： 1338-1350 2019.7
Therapeutic efficacy of rituximab for the management of adult-onset steroid-dependent nephrotic syndrome: a retrospective study. Reviewed
Katsuno T, Masuda T, Saito S, Kato N, Ishimoto T, Kato S, Kosugi T, Tsuboi N, Kitamura H, Tsuzuki T, Ito Y, Maruyama S.
Clin Exp Nephrol. Vol. 23 ( 2 ) page： 207 - 214 2019.2
The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity. Reviewed
Kameyama H, Uchimura K, Yamashita T, Kuwabara K, Mizuguchi M, Hung SC, Okuhira K, Masuda T, Kosugi T, Ohgita T, Saito H, Ando Y, Nishitsuji K.
Am J Pathol. Vol. 189 ( 2 ) page： 308 - 319 2019.2
Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis. Reviewed
Katsuno T, Ozaki T, Ozeki T, Hachiya A, Kim H, Kato N, Ishimoto T, Kato S, Kosugi T, Tsuboi N, Mizuno M, Ito Y, Maruyama S.
Clin Exp Nephrol. Vol. 22 ( 6 ) page： 1341 - 1350 2018.12
Serum alpha cKlotho as a Predictor of Graft Dysfunction After Kidney Transplantation
Tsujita M., Kosugi T., Masuda T., Okada M., Futamura K., Hiramitsu T., Goto N., Shunji N., Watarai Y., Maruyama S.
TRANSPLANTATION PROCEEDINGS Vol. 50 ( 10 ) page： 3440 - 3444 2018.12
The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases.
Mori Y, Masuda T, Kosugi T, Yoshioka T, Hori M, Nagaya H, Maeda K, Sato Y, Kojima H, Kato N, Ishimoto T, Katsuno T, Yuzawa Y, Kadomatsu K, Maruyama S
Clinical and experimental nephrology Vol. 22 ( 4 ) page： 815 - 824 2018.8
Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice. Reviewed
Doke T, Ishimoto T, Hayasaki T, Ikeda S, Hasebe M, Hirayama A, Soga T, Kato N, Kosugi T, Tsuboi N, Lanaspa MA, Johnson RJ, Kadomatsu K, Maruyama S.
Metabolism. Vol. 85 page： 161 - 170 2018.8
Efficacy of urinary midkine as a biomarker in patients with acute kidney injury
Hayashi Hiroki, Sato Waichi, Kosugi Tomoki, Nishimura Kunihiro, Sugiyama Daisuke, Asano Naoko, Ikematsu Shinya, Komori Kimihiro, Nishiwaki Kimitoshi, Kadomatsu Kenji, Matsuo Seiichi, Maruyama Shoichi, Yuzawa Yukio
CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 21 ( 4 ) page： 597-607 2017.8
Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis
Masuda Tomohiro, Maeda Kayaho, Sato Waichi, Kosugi Tomoki, Sato Yuka, Kojima Hiroshi, Kato Noritoshi, Ishimoto Takuji, Tsuboi Naotake, Uchimura Kenji, Yuzawa Yukio, Maruyama Shoichi, Kadomatsu Kenji
AMERICAN JOURNAL OF PATHOLOGY Vol. 187 ( 4 ) page： 740-751 2017.4
Sato, N; Katsuno, T; Mori, M; Saito, S; Kato, N; Ishimoto, T; Kosugi, T; Tsuboi, N; Ito, Y; Maruyama, S
RHEUMATOLOGY Vol. 56 page： 75 - 75 2017.3
Single-dose Rituximab Therapy for Refractory Idiopathic Membranous Nephropathy: A Single-center Experience
Katsuno Takayuki, Ozaki Takenori, Kim Hangsoo, Kato Noritoshi, Suzuki Yasuhiro, Akiyama Shinichi, Ishimoto Takuji, Kosugi Tomoki, Tsuboi Naotake, Ito Yasuhiko, Maruyama Shoichi
INTERNAL MEDICINE Vol. 56 ( 13 ) page： 1679-1686 2017
Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis. Reviewed
Endo N, Tsuboi N, Furuhashi K, Shi Y, Du Q, Abe T, Hori M, Imaizumi T, Kim H, Katsuno T, Ozaki T, Kosugi T, Matsuo S, Maruyama S.
Nephrol Dial Transplant. Vol. 31 ( 12 ) page： 2023-2033 2016.12
Randomized control trial for the assessment of the anti-albuminuric effects of topiroxostat in hyperuricemic patients with diabetic nephropathy (the ETUDE study). Reviewed
Kato S, Ando M, Mizukoshi T, Nagata T, Katsuno T, Kosugi T, Tsuboi N, Maruyama S.
Nagoya J Med Sci. Vol. 78 ( 2 ) page： 135-142 2016.5
Efficacy of urinary midkine as a biomarker in patients with acute kidney injury. Reviewed
Hayashi H, Sato W, Kosugi T, Nishimura K, Sugiyama D, Asano N, Ikematsu S, Komori K, Nishiwaki K, Kadomatsu K, Matsuo S, Maruyama S, Yuzawa Y.
Clin Exp Nephrol. 2016
Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth in Models of Acute Kidney Injury. Reviewed
Hattori Y, Kim H, Tsuboi N, Yamamoto A, Akiyama S, Shi Y, Katsuno T, Kosugi T, Ueda M, Matsuo S, Maruyama S.
PLoS One. Vol. 10 ( 10 ) page： e0140121 2015.10
Increase of Antimyeloperoxidase Antineutrophil Cytoplasmic Antibody (ANCA) in Patients with Renal ANCA-associated Vasculitis: Association with Risk to Relapse. Reviewed
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.
J Rheumatol. 2015.9
Fructose and uric acid in diabetic nephropathy. Invited Reviewed
Bjornstad P, Lanaspa MA, Ishimoto T, Kosugi T, Kume S, Jalal D, Maahs DM, Snell-Bergeon JK, Johnson RJ, Nakagawa T.
Diabetologia. Vol. 58 ( 9 ) page： 1993-2002 2015.9
Neutrophil/lymphocyte ratio as a predictor of cardiovascular events in incident dialysis patients: a Japanese prospective cohort study. Reviewed
Abe T, Kato S, Tsuruta Y, Sugiura S, Katsuno T, Kosugi T, Tsuboi N, Matsuo S, Maruyama S.
Clin Exp Nephrol. Vol. 19 ( 4 ) page： 718-724 2015.8
The efficacy of tolvaptan as a diuretic for chronic kidney disease patients. Reviewed
Tanaka A, Katsuno T, Ozaki T, Sakata F, Kato N, Suzuki Y, Kosugi T, Kato S, Tsuboi N, Sato W, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S.
Acta Cardiol. Vol. 70 ( 2 ) page： 217-223 2015.4
Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids. Reviewed
Sato Y, Sato W, Maruyama S, Wilcox CS, Falck JR, Masuda T, Kosugi T, Kojima H, Maeda K, Furuhashi K, Ando M, Imai E, Matsuo S, Kadomatsu K.
J Am Soc Nephrol. 2015
CD147/Basigin limits lupus nephritis and TH 17 cell differentiation by inhibiting the IL-6/STAT3 pathway. Reviewed
Maeda K, Kosugi T, Sato W, Kojima H, Sato Y, Kamimura D, Kato N, Tsuboi N, Yuzawa Y, Matsuo S, Murakami M, Maruyama S, Kadomatsu K.
Arthritis Rheumatol. 2015
Comparison of kidney disease: improving global outcomes and acute kidney injury network criteria for assessing patients in intensive care units. Reviewed
Shinjo H, Sato W, Imai E, Kosugi T, Hayashi H, Nishimura K, Nishiwaki K, Yuzawa Y, Matsuo S, Maruyama S.
Clin Exp Nephrol. Vol. 18 ( 5 ) page： 737-45 2014.10
Patient age and the prognosis of idiopathic membranous nephropathy. Reviewed
Yamaguchi M, Ando M, Yamamoto R, Akiyama S, Kato S, Katsuno T, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S.
PLoS One Vol. 9 ( 10 ) page： e110376 2014.8
Smoking is a risk factor for the progression of idiopathic membranous nephropathy. Reviewed
Yamaguchi M, Ando M, Yamamoto R, Akiyama S, Kato S, Katsuno T, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S.
PLoS One Vol. 9 ( 6 ) page： e100835 2014.6
Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects Against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency. Reviewed
Shi Y, Tsuboi N, Furuhashi K, Du Q, Horinouchi A, Maeda K, Kosugi T, Matsuo S, Maruyama S.
J Immunol 2014
CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint. Invited Reviewed
Kosugi T, Maeda K, Sato W, Maruyama S, Kadomatsu K.
Nephrol Dial Transplant 2014
Neutrophil/lymphocyte ratio as a predictor of cardiovascular events in incident dialysis patients: a Japanese prospective cohort study. Reviewed
Abe T, Kato S, Tsuruta Y, Sugiura S, Katsuno T, Kosugi T, Tsuboi N, Matsuo S, Maruyama S.
Clin Exp Nephrol. 2014
CD147/basigin reflects renal dysfunction in patients with acute kidney injury. Reviewed
Nagaya H, Kosugi T, Maeda-Hori M, Maeda K, Sato Y, Kojima H, Hayashi H, Kato N, Ishimoto T, Sato W, Yuzawa Y, Matsuo S, Kadomatsu K, Maruyama S.
Clin Exp Nephrol. 2013.12
High fat and high sucrose (western) diet induce steatohepatitis that is dependent on fructokinase. Reviewed
Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, McMahan RH, Abdelmalek MF, Rosen HR, Jackman MR, Maclean PS, Diggle CP, Asipu A, Inaba S, Kosugi T, Sato W, Maruyama S, Sánchez-Lozada LG, Sautin YY, Hill JO, Bonthron DT, Johnson RJ.
Hepatology 2013.6
Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Reviewed
Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzicky P, Rivard C, Inaba S, Roncal-Jimenez CA, Bales ES, Diggle CP, Asipu A, Petrash JM, Kosugi T, Maruyama S, Sanchez-Lozada LG, McManaman JL, Bonthron DT, Sautin YY, Johnson RJ.
Nat Commun. ( 4 ) page： 2434 2013
Uncoupling of VEGF with endothelial NO as a potential mechanism for abnormal angiogenesis in the diabetic nephropathy. Reviewed
Nakagawa T, Sato W, Kosugi T, Johnson RJ.
J Diabetes Res. 2013
Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Reviewed
Ishimoto T, Shimada M, Gabriela G, Kosugi T, Sato W, Lee PY, Lanaspa MA, Rivard C, Maruyama S, Garin EH, Johnson RJ
Nephrol Dial Transplant. 2012.12
Deficiency of Growth Factor Midkine Exacerbates Necrotizing Glomerular Injuries in Progressive Glomerulonephritis. Reviewed
Kojima H, Kosugi T, Sato W, Sato Y, Maeda K, Kato N, Kato K, Inaba S, Ishimoto T, Tsuboi N, Matsuo S, Maruyama S, Yuzawa Y, Kadomatsu K.
Am J Pathol. 2012.11
Distribution of hydrogen sulfide (H(2)S)-producing enzymes and the roles of the H(2)S donor sodium hydrosulfide in diabetic nephropathy. Reviewed
Yamamoto J, Sato W, Kosugi T, Yamamoto T, Kimura T, Taniguchi S, Kojima H, Maruyama S, Imai E, Matsuo S, Yuzawa Y, Niki I.
Clin Exp Nephrol. 2012.8
A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin. Reviewed
Ito I, Ito Y, Mizuno M, Suzuki Y, Yasuda K, Ozaki T, Kosugi T, Yasuda Y, Sato W, Tsuboi N, Maruyama S, Imai E, Matsuo S.
Clin Exp Nephrol. Vol. 16 ( 3 ) page： 490-494 2012.6
Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Reviewed
Ishimoto T, Lanaspa MA, Le MT, Garcia GE, Diggle CP, Maclean PS, Jackman MR, Asipu A, Roncal-Jimenez CA, Kosugi T, Rivard CJ, Maruyama S, Rodriguez-Iturbe B, Sanchez-Lozada LG, Bonthron DT, Sautin YY, Johnson RJ
Proc Natl Acad Sci U S A. Vol. 109 ( 11 ) page： 4320-4325 2012.3
Midkine and the kidney; health and diseases Invited Reviewed
Kosugi T and Sato W
Nephrol. Dial Transplant. 2011.12
Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease. Reviewed
Sato W, Tanabe K, Kosugi T, Hudkins K, Lanaspa MA, Zhang L, Campbell-Thompson M, Li Q, Long DA, Alpers CE, Nakagawa T.
American Journal of Pathology 2011.5
Growth factor Midkine is involved in the pathogenesis of renal injury induced by protein overload containing endotoxin. Reviewed
Kato K, Kosugi T, Sato W, Arata-Kawai H, Ozaki T, Tsuboi N, Ito I, Tawada H, Yuzawa Y, Matsuo S, Kadomatsu K, Maruyama S.
Clin Exp Nephrol. 2011.3
Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction. Reviewed
Kato N, Kosugi T, Sato W, Ishimoto T, Kojima H, Sato Y, Sakamoto K, Maruyama S, Yuzawa Y, Matsuo S, Kadomatsu K.
American Journal of Pathology. Vol. 178 ( 2 ) page： 572-9 2011.2
Endothelial dysfunction as a potential contributor in diabetic nephropathy. Reviewed
Nakagawa T, Tanabe K, Croker BP, Johnson RJ, Grant MB, Kosugi T, Li Q.
Nature Review Nephrology. Vol. 7 ( 1 ) page： 36-44 2011.1
Endothelial von Willebrand factor release due to eNOS deficiency predisposes to thrombotic microangiopathy in mouse aging kidney. Reviewed
Nakayama T, Sato W, Yoshimura A, Zhang L, Kosugi T, Campbell-Thompson M, Kojima H, Croker BP, Nakagawa T.
American Journal of Pathology. Vol. 176 ( 5 ) page： 2198-208 2010.5
Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice. Reviewed
Kosugi T, Nakayama T, Li Q, Chiodo VA, Zhang L, Campbell-Thompson M, Grant M, Croker BP, Nakagawa T.
Am J Physiol Renal Physiol. Vol. 298 ( 3 ) page： F609-616 2010.3
Dietary fructose causes tubulointerstitial injury in the normal rat kidney. Reviewed
Nakayama T, Kosugi T, Gersch M, Connor T, Sanchez-Lozada LG, Lanaspa MA, Roncal C, Perez-Pozo SE, Johnson RJ, Nakagawa T.
Am J Physiol Renal Physiol. Vol. 298 ( 3 ) page： F712-20 2010.3
eNOS knockout mice with advanced diabetic nephropathy have less benefit from renin-angiotensin blockade than from aldosterone receptor antagonists. Reviewed
Kosugi T, Heinig M, Nakayama T, Matsuo S, Nakagawa T.
American Journal of Pathology Vol. 176 ( 2 ) page： 619-629 2010.2
Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice. Reviewed
Kosugi T, Nakayama T, Heinig M, Zhang L, Yuzawa Y, Sanchez-Lozada LG, Roncal C, Johnson RJ, Nakagawa T.
Am J Physiol Renal Physiol. Vol. 297 ( 2 ) page： F481-488 2009.8
The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion Reviewed
Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W, Miwa Y, Sakamoto K, Matsuo S, Kadomatsu K.
Journal of American Society of Nephrology Vol. 20 ( 7 ) page： 1565-1576 2009.7
Abnormal angiogenesis in diabetic nephropathy. Reviewed
Nakagawa T, Kosugi T, Haneda M, Rivard CJ, Long DA.
Diabetes. Vol. 58 ( 7 ) page： 1471-8 2009.7
The growth factor midkine regulates the renin-angiotensin system in mice. Reviewed
Hobo A, Yuzawa Y, Kosugi T, Kato N, Asai N, Sato W, Maruyama S, Ito Y, Kobori H, Ikematsu S, Nishiyama A, Matsuo S, Kadomatsu K.
Journal of Clinical Investigation Vol. 119 ( 6 ) page： 1616-1625 2009.6
Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse. Reviewed
Nakayama T, Sato W, Kosugi T, Zhang L, Campbell-Thompson M, Yoshimura A, Croker BP, Johnson RJ, Nakagawa T.
American Jouenal of Physiology Renal Physiology Vol. 296 ( 2 ) page： F317-27 2009.2
Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, in diabetic eNOS knockout mice. Reviewed
Kosugi T, Heinig M, Nakayama T, Connor T, Yuzawa Y, Li Q, Hauswirth WW, Grant MB, Croker BP, Campbell-Thompson M, Zhang L, Atkinson MA, Segal MS, Nakagawa T.
American Journal of Pathology Vol. 174 ( 4 ) page： 1221-1229 2009.2
Uric acid and hypertension: an age-related relationship? Reviewed
Kosugi T, Nakagawa T, Kamath D, Richard RJ
J Hum Hypertens. Vol. 23 ( 2 ) page： 75-76 2009.2
Fructose induces the inflammatory molecule ICAM-1 in endothelial cells Reviewed
Glushakova O, Kosugi T, Roncal C, Mu W, Heinig M, Cirillo P, Sánchez-Lozada LG, Johnson RJ, Nakagawa T.
Journal of American Society of Nephrology Vol. 19 ( 9 ) page： 1712-1720 2008.9
Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy. Reviewed
Yuzawa Y, Niki I, Kosugi T, Maruyama S, Yoshida F, Takeda M, Tagawa Y, Kaneko Y, Kimura T, Kato N, Yamamoto J, Sato W, Nakagawa T, Matsuo S.
Journal of American Society of Nephrology Vol. 19 ( 9 ) page： 1701-1711 2008.9
The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy. Reviewed
Sato W, Kosugi T, Zhang L, Roncal CA, Heinig M, Campbell-Thompson M, Yuzawa Y, Atkinson MA, Grant MB, Croker BP, Nakagawa T.
Laboratory Investigation Vol. 88 ( 9 ) page： 949-961 2008.9
Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy. Reviewed
Kosugi T, Yuzawa Y, Sato W, Arata-Kawai H, Suzuki N, Kato N, Matsuo S, Kadomatsu K.
Labratory Investigation Vol. 87 ( 9 ) page： 903-913 2007.9
Growth factor midkine is involved in the pathogenesis of diabetic nephropathy. Reviewed
Kosugi T, Yuzawa Y, Sato W, Kawai H, Matsuo S, Takei Y, Muramatsu T, Kadomatsu K.
American Journal of Pathology Vol. 168 ( 1 ) page： 9-19 2006.1
Lack of the growth factor midkine enhances survival against cisplatin-induced renal damage. Reviewed
Kawai H, Sato W, Yuzawa Y, Kosugi T, Matsuo S, Takei Y, Kadomatsu K, Muramatsu T.
American Journal of Pathology. Vol. 165 ( 5 ) page： 1603-12 2004.11
Autopsy case of the cerebellar form of progressive multifocal leukoencephalopathy without immunodeficiency. Reviewed
Arai Y, Tsutsui Y, Nagashima K, Shinmura Y, Kosugi T, Wakai M, Nishikage H, Yamamoto J.
Neuropathology. Vol. 22 ( 1 ) page： 48-56 2002.3
aHUS早期診断及び抗補体薬の適応判断に必要な補体機能検査開発
Grant number：22K08349 2022.4 - 2025.3
科学研究費助成事業 基盤研究(C)
加藤 規利, 前田 佳哉輔, 丸山 彰一, 水野 正司, 古橋 和拡, 小杉 智規
Authorship：Coinvestigator(s)
aHUSは血液中ではなく、血管内皮細胞膜上での無秩序な補体活性化が問題であり、単純な採血で評価できないところに検査開発の難しさがある。我々は、2020年より開始したaHUS全国調査研究で登録のあった症例の血漿から、細胞外小胞（Exosomes）を精製し、Exosomes上の補体関連タンパクを測定し、細胞膜上の補体活性を評価する。またex vivoでaHUS患者の血漿と血管内皮細胞株との反応系にエクリズマブを添加することにより、実際に薬剤を投与する前に、治療反応性を見極める。
難治性ネフローゼ症候群のエネルギー代謝動態から迫る新たな治療標的の探索
Grant number：22K08308 2022.4 - 2025.3
科学研究費助成事業 基盤研究(C)
前田 佳哉輔, 佐藤 由香, 小杉 智規, 加藤 規利
Authorship：Coinvestigator(s)
進行性ポドサイト障害による難治性ネフローゼ症候群は病態解明と治療標的の探索が課題であり、申請者らは進行性ポドサイト障害のシグナル経路の同定、ポドサイト標的デリバリーシステムの開発を行っており、ネフローゼ症候群において治療抵抗例で解糖系由来のエネルギー産生が低下し、ポドサイト障害を誘導する事を、治療反応例では解糖系由来のエネルギー産生は維持され、障害が抑制される結果を得ている。本課題では、①ポドサイト障害時の解糖系のエネルギー代謝機構の解明、②治療抵抗/反応例のエネルギー代謝ネットワークの比較・解析、③治療抵抗例のエネルギー産生機構に関する液性因子の同定を行い、有効な治療標的の探索をめざす。
慢性腎臓病患者における生体内細菌叢をターゲットにした新規抗老化療法の開発
Grant number：22K08328 2022.4 - 2025.3
科学研究費助成事業 基盤研究(C)
加藤 佐和子, 丸山 彰一, 今泉 貴広, 小杉 智規
Authorship：Coinvestigator(s)
慢性腎臓病（CKD）患者の表現系は老化に見られる諸変化に酷似している。通常の維持血液透析患者（従来透析）と長時間透析患者、保存期腎不全患者は、尿毒症にさらされている強度や条件が異なる。尿毒症存在下において、どのような外的・内的環境負荷（Allostatic load）が免疫学的変調と慢性炎症をきたし、Microbiomeの変調をきたすのか、老化の指標となる遺伝子保護の不調（テロメア消耗）に関与しているか解析し、実際の心疾患、感染症、死亡率と比較することにより、腸内細菌叢の改善をターゲットとしたCKD患者の新規治療戦略の構築を目指すものである。
フルクトース代謝を標的とした糖尿病性腎臓病の病態解明と新規治療法の開発
Grant number：21K08254 2021.4 - 2024.3
科学研究費助成事業 基盤研究(C)
石本 卓嗣, 小杉 智規, 古橋 和拡, 平山 明由
Authorship：Coinvestigator(s)
これまでに、グルコースより内因性に産生される過剰なフルクトース代謝が糖尿病性腎臓病（DKD）およびメタボリック症候群・脂肪肝を進展させることを報告し、フルクトース代謝酵素KHK-Cを抑制する治療法の開発に取り組んできた。本研究は、①腎尿細管のKHK-C依存的フルクトース代謝の抑制によるDKDの進展抑制効果およびその機序を解明し、②高い酵素耐性を持つ非環状型人工核酸を用いたKHK-Cを阻害する核酸医薬を開発する。
１） KHK-C依存的フルクトース代謝の抑制による、異常解糖系の改善・DKDの進展抑制効果を解明する。
CRISPR-Cas9システムにより作成したKHK-Cのみを欠損するKHK-C KOマウスおよびKHK-A KOマウス、KHK-A/C KOマウス、野生型マウスを用い、2ヶ月令時にストレプトゾトシン誘導性の糖尿病モデルを作成した。ストレプトゾトシン投与半年後に腎障害の評価を行う予定である。また、KHK-Cを強制発現した不死化近位尿細管細胞HK-2にフルクトース・グルコース刺激を行い、過剰なフルクトース代謝の解糖系（ECAR）・ミトコンドリア呼吸（OCR）への影響を、細胞外フラックスアナライザーにより解析している。
２）KHK-Cを選択的に阻害する核酸医薬および低分子化合物を作成し、DKDおよびMS・脂肪肝に対する新規治療法を開発する。
KHK-Cを選択的に阻害するsiRNAを作成し、KHK-Cのノックダウン効率およびKHK-Aへの影響を含めたオフターゲット効果を評価した。同様の配列を用い、KHK-Cを選択的に阻害するアンチセンスオリゴヌクレオチドを作成した。マウスへの投与による評価を開始している。
KHK-Cノックアウトマウスを含めた複数のノックアウトマウス（KHK-C KO、KHK-A KO、KHK-A/C KO）のコロニーを拡大し、野生型マウス含めてストレプトゾトシン誘導性の糖尿病モデルをすでに作成しており、現在、評価時期の検討しつつ経過をみている。また、フラックスアナライザーによる実験評価系も安定しつつあり、評価を進めている。また、KHK-Cを選択的に阻害する核酸については、siRNAは有用な配列が同定できている。アンチセンスオリゴヌクレオチドについても概ね有効性を確認しているが、さらなる抑制効率の向上のために検討を進めている。
１）KHK-C依存的フルクトース代謝の抑制による、異常解糖系の改善・DKDの進展抑制効果を解明する。
ストレプトゾトシン誘導性の糖尿病モデルについて、随時、蛋白尿や尿細管障害マーカーを測定し、野生型マウスにおける腎障害モデルの疾患重症度を確認しつつ屠殺時期を最終決定し、解析する。培養細胞を用いたフラックスアナライザーによる検討も引き続き進める。
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２）KHK-Cを選択的に阻害する核酸医薬および低分子化合物を作成し、DKDおよびMS・脂肪肝に対する新規治療法を開発する。
KHK-Cを選択的に阻害する核酸について、アンチセンスオリゴヌクレオチドによるよく成功率を更に高められる配列・塩基長・核酸修飾について検討を続ける。マウスへの核酸の全身投与については、アンチセンスオリゴヌクレオチドの皮下投与など、投与経路を含めた評価を行い、腎・肝におけるKHK-C選択的阻害効果を検討する。
高温環境によるCKD発症の病態解明と細胞老化制御を介した治療標的の探索
Grant number：20K08607 2020.4 - 2023.3
科学研究費助成事業 基盤研究(C)
佐藤 由香, 石本 卓嗣, 前田 佳哉輔, 小杉 智規
Authorship：Coinvestigator(s)
暑い環境での体温上昇が慢性腎臓病(CKD)を惹起進展させるという新しい病態が報告されている。日本でも夏の気温上昇に伴い、熱中症の発症率・死亡率が特に高齢者で増加しており、熱ストレスによる腎障害の病態解明は本邦でも望まれる。申請者らは、繰り返す高温暴露により腎障害に進展する動物モデルを作成した。同モデルで長寿遺伝子Sirtuin１(Sirt1)の低下を認めたことから、病態への老化の関与が疑われた。そこで本研究では、まずは個体老化に注目し加齢が熱ストレス誘導性腎障害のリスクであることを老化促進マウスを使い検討する。さらに細胞老化における熱ストレスの分子病態を解明し、新たな治療標的を探索する。
熱ストレスの慢性的な暴露で腎障害に進展する新しい病態の機序解明のため、研究代表者らは過去に熱ストレス誘因性CKD動物モデルを確立したことを報告した（Kidney Int. 2013, Am J Physiol Renal Physiol. 2019）。既報では、Heat stress下では飲水や餌の摂取ができない小さいHeat chamberを用いたため、連続したHeat stressを与えることはできなかった。今回、新たにHeat stress下で飼育可能な小動物用温度調節機能付チャンバーを購入し、昇熱ストレス下で連続飼育することで、実際の昇熱ストレスに近いモデルを作成した。
38度の高温環境で3時間連続で飼育後に、1時間の室温23℃環境の休憩をはさみ、再び38℃高温環境を3時間連続で飼育するモデルとした。まずは、新規モデルで昇熱による急性障害であるHeat strokeによる兆候や死亡例が認めないか確認した。次に、7時間の昇熱ストレス終了直前に、直腸温は環境温と同定度の38℃まで上昇していることを確認した。
さらに加齢とHeat stressの探求のため、生後10か月の高齢マウスを用いて実験を行った。8週齢の若年および40週齢の高齢のC57BL6の雄マウスに、前述の室温38℃高温環境を3時間暴露後、室温23℃を1時間の休憩後、再び38℃高温環境3時間の、1日当たり計6時間の高温暴露を連日行い、6か月後にサクリファイスを行った。若年マウスでは6か月のHeat stress暴露後でも腎機能悪化は認めなかったが、高齢マウスでは有意差をもって腎機能の悪化を認めた。また末梢血の好中球数は、高齢マウスで非暴露群・暴露群ともに若年マウスのコントロール群(非暴露群)より高値であったが、若年マウスの暴露群で好中球数が高齢マウスと同様に上昇していることが見いだされた.
初年度は、加齢促進マウスを用いた研究、若年マウスでの虚血性AKIに対する昇熱ストレスの研究を行ったが、加齢促進マウスで既報のような腎障害は認めず、若年マウスの虚血性AKIの結果も有意な結果が得られなかった。本年度から加齢マウスを購入し、再実験を行ったため、当初の研究から遅れを来している。
加齢マウスでの再実験では、仮説通り加齢による腎障害促進の結果を得ており、解析を進めていく。
Usefulness of Basigin as a novel therapeutic target for diabetic kidney and liver diseases
Grant number：20K08632 2020.4 - 2023.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Authorship：Principal investigator
Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）
Novel CaMK4-mediated podocyte-specific therapy in refractory renal disease
Grant number：19K08723 2019.4 - 2022.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Maeda Kayaho
Authorship：Coinvestigator(s)
We elucidated the role of CaMK4 in refractory nephrotic syndrome such as focal segmental glomerulosclerosis, and developed podocyte-specific therapy. The findings using podocyte-specific CaMK4-deficient mice showed that CaMK4 in podocytes is involved in podocyte cell death and induces more proteinuria, and podocyte-directed nanoparticles with a CaMK4 inhibitor showed the efficacy compared to administration without nanoparticles.
Grant number：19K08700 2019.4 - 2022.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Kato Sawako
Authorship：Coinvestigator(s)
We analyzed bacterial DNA fragments in the circulating leukocytes collected from the patients who had just started dialysis therapy and one year after dialysis initiation. The bacterial strains in the circulating leukocytes at the start of dialysis differed greatly according to the primary disease of renal failure (diabetes mellitus, polycystic kidney, nephrosclerosis, chronic nephritis). There was no difference in bacterial strains between diabetic and non-diabetic, or patients with and without a history of cardiovascular disease.Next, we compared the bacterial genera among patients at the start dialysis, those one year after the start of dialysis therapy and healthy subjects. We found the difference in key bacterial genera involved with induction of inflammation between dialysis patients and healthy subjects. In addition, there was a correlation between the increase in serum calcium levels at the start of dialysis and the growth of Bacillus bacteria.
Grant number：19K08701 2019.4 - 2021.3
科学研究費助成事業 基盤研究(C)
小島 博, 水野 正司, 鈴木 康弘, 勝野 敬之, 小杉 智規
Authorship：Coinvestigator(s)
急性腎障害に補体とT細胞免疫はそれぞれ役割を果たすが、両者の相互作用については未だ不明である。最近補体が、樹状細胞(DC)の抗原提示から始まるナイーブT細胞(Th0)の分化増殖を調節することが注目され、DCとTh0細胞の会合に重要なCC-ケモカインレセプタ7(CCR7)発現が、補体活性化により誘導される可能性が報告されている。研究代表者らは補体C5aに注目してこれまで研究を進めてきたが、一方、CCR7欠損マウスで腎虚血再灌流モデル(IRI)において、野生型に比して腎障害が抑止されることを見出している。本研究において、CCR7を介したC5a経路の正の制御機構の存在を明らかにする。
本研究課題は、獲得免疫において重要な役割を果たすCCR7に注目して、補体系とT細胞免疫の相互作用の解明を目指した。CCR7は、樹状細胞（DC）とT細胞の会合や、DCの機能調節に役割を有し、T細胞免疫に重要な役割を果たす。一方で、補体H因子の存在がDCのCCR7発現低下をもたらした報告から、補体活性化がCCR7発現上昇を来す可能性が示唆されるが、その分子機構や意義は不明である。
CCR7欠損、及び野生型マウスを用いて、IRIモデル、CLPモデルを作成し、結果1、2を得た。結果1：IRIモデルでは、CCR7欠損マウスにおいて、腎障害が軽い。結果2：CLPモデルでは、CCR7欠損マウスにおいて、腎障害が重篤であり、個体生存率も低い。
IRI、CLPモデル何れにおいても、腎障害の明らかな差が、獲得免疫が作動する前の超急性期に出現したので、CCR7が自然免疫においても重要な役割を果たす可能性が示唆された。NKT細胞が、DAMPs・PAMPs刺激に迅速に反応することに注目し、CCR7の有無が、NKT細胞の機能発現に関与していると推測した。補体系とNKT細胞はともに、ナイーブT細胞の分化、増殖に関わり、その後の獲得免疫反応を決定づけるので、NKT細胞から分泌され、ナイーブT細胞分化に関わるサイトカイン、特にインターフェロン-γ（IFN-γ）に注目した。
NKT細胞特異的リガンドであるαガラクトシルセラミド（αGalCer）を、CCR7欠損、及び野生型マウスに投与し、結果3を得た。結果3：αGalCer刺激において、CCR7欠損マウスは血清IFN-γ濃度とNKT細胞IFN-γ mRNA発現の両者が、野生型に比して、低値である。
C5a-C5R axisがIFN-γ産生に関わることは既に報告されていたが、CCL19/21-CCR7 axisもNKT細胞のIFN-γ産生に関わることが示唆された。
Grant number：17K09695 2017.4 - 2020.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Kosugi Tomoki
Authorship：Principal investigator
Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）
In the present study, we aimed to elucidate the underlying mechanisms of chronic kidney disease (CKD) and hepatic steatosis caused by nutritional overburden more in details. Therefore, we investigated the role of CD147/Basigin (BSG) to maintain intracellular energy homeostasis, using high fat diet (HFD)-induced wild-type and BSG gene-deficient (BSGKO) mice. In the kidneys of BSGKO mice, vacuolar degeneration of tubular epithelial cells and accumulation of lipofuscin-like substances were remarkably suppressed. These findings might be due to the phenomena that transport of the substrates such as pyruvate and lactate in the cells was suppressed by BSG deficits subsequently leading to the the reduction of TCA cycle intermediates and enhanced ketogenesis through activation of free fatty acid beta oxidation. In the setting, augmented BSG protein might be due to the promotion of autophagy, but not translocation to nuclei.
血管内皮障害を呈する腎疾患におけるSulf2の機能解析と新たな治療戦略の探求
Grant number：17K09694 2017.4 - 2019.3
科学研究費助成事業 基盤研究(C)
増田 智広, 丸山 彰一, 内村 健治, 小杉 智規
Authorship：Coinvestigator(s)
細胞外スルファターゼSulf2は、分子量約130kDaの分泌型酵素で細胞外での膜タンパクに付着している糖鎖の脱硫酸化を担いWnt, BMP, GDNF, FGFというヘパリン結合性因子のシグナル伝達を制御する物質である。
腎臓領域ではSulf1およびSulf2が細胞外基質蓄積を制御し糖尿病性腎症悪化に寄与するとの既報がある。また、ヘパラン硫酸-S-ドメインの蓄積は原線維形成を促進し、腎臓での細胞毒性を促進するという知見が加わった。上記よりSulf2Tgは腎保護に寄与すると仮説を立て私はヒトSulf2全身強制発現マウス(HSulf2Tg)と血管内皮細胞特異的Sulf2強発現 (Tie2-Cre/Sulf2)を用いて、腎機能にどのように関与するか機序解明を目指した。
初年度の計画としてはHSulf2Tgの腎障害惹起時に表現型の確認。腎障害を惹起していない野生型とHSulf2Tgを比較し双方ともに腎機能が正常であった。また、腎障害モデルとして交付申請書に記載した抗基底膜抗体により直接的に糸球体内皮細胞を障害する加速型馬杉腎炎モデルに加えて、アドリアマイシン腎症モデル、糖尿病モデルを作成。いずれのモデルにおいても、HSulf2Tgの方が 尿素窒素・クレアチニン・尿タンパクが低値であった。しかし、Tie2-Cre/Sulf2は野生型と比して尿素窒素・クレアチニン・尿タンパクのいずれも差異は認めなかった。
Establishment of renal protection strategy by icosapentaic acid (EPA) and elucidation of mechanism of action
Grant number：16K09633 2016.4 - 2019.3
Hayashi Hiroki
Authorship：Coinvestigator(s)
Although epidemiological data showing the association between inadequate intake of Eeicosapentaenoic acid (EPA) and the risk of cardiovascular disease are abundant, interventional studies are limited. The aim of present study was to determine the effect of EPA supplementation on renal function in patients with stage G3 and G4 CKD. In patients with >0.5g/gCr proteinuria, two years supplementation with EPA led to significant protection in ⊿eGFR (p<0.05) compared with the controls.
Development of novel antihypertensive therapy with tissue protection in renal and cardiovascular diseases through elucidation of MK-EETs blood pressure regulation mechanism
Grant number：16K09609 2016.4 - 2019.3
Kato sawako
Authorship：Coinvestigator(s)
In a system aiming at deep observation of the living body using multiphoton confocal laser microscope A1R MP (Nikon), administration of epoxy eicosatrienoic acids (EETs) inhibitor and adenosine inhibitor, induced the vasoconstrictive action in Midkine (MK) deficient mice. The blood vessels were contracted and blood flow was decreased, as blood pressure increased. The blood flow rate was rising. On the other hand, when a nicotinic acetylcholine receptor inhibitor was administered to evaluate the sympathetic nervous system, blood pressure dropped in MK deficient mice, indicating an increase in blood flow. MK has been shown to regulate renal and blood pressure via a vasodilator.
Investigation of safer methods of therapeutic miRNA and exosomes
Grant number：16K09610 2016.4 - 2019.3
Kato Noritoshi
Authorship：Coinvestigator(s)
We investigated the pathophysiological role of exogenously applied microRNA (miRNA) in sepsis-induced multiple organ injury. In vitro, we tested possible miRNAs which suppressed the production of pro-inflammatory cytokines. Of these, miR-146a displayed the highest suppressive effect. Sepsis was induced in mice via cecal ligation and puncture (CLP) and an intravenous injection of a complex of miR-146a-expressing plasmid and polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury, and led to increased survival from sepsis. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation in the spleen. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury.
The role of fructose metabolism in the development of chronic kidney disease and hypertension.
Grant number：15K09255 2015.4 - 2018.3
ISHIMOTO TAKUJI
Authorship：Coinvestigator(s)
The aim of this study is to elucidate the role of fructose metabolism by the primary enzyme of fructose, ketohexokinase (KHK) in hypertension. In this study, by using KHK knockout mice (KHK-KO), we found that the combination of fructose and high salt induced the elevation of blood pressure with decrease of sodium excretion and increase of mRNA expression of NHE3 in kidney in wild type mice (WT), but not in KHK-KO mice, and that fructose stimulation increased NHE activity accompanied by a decrease in intracellular cAMP that is dependent on KHK. These results suggest that fructose metabolism by KHK is involved in the development of salt-sensitive hypertension through increases of renal sodium reabsorption by NHE3.
CD147による腎エネルギー代謝機構の解明と臓器相関に対する治療法の探求
2014.4 - 2017.3
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
