Faculty Profiles - FURUHASHI Kazuhiro

Generation of functional lungs via conditional blastocyst complementation using pluripotent stem cells. Reviewed

Mori M, Furuhashi K, Danielsson JA, Hirata Y, Kakiuchi M, Lin CS, Ohta M, Riccio P, Takahashi Y, Xu X, Emala CW, Lu C, Nakauchi H, Cardoso WV

Nature medicine Vol. 25 ( 11 ) page： 1691 - 1698 2019.11

CD150<sup>high</sup> Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine. Reviewed

Hirata Y, Furuhashi K, Ishii H, Li HW, Pinho S, Ding L, Robson SC, Frenette PS, Fujisaki J

Cell stem cell Vol. 22 ( 3 ) page： 445 - 453.e5 2018.3

Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life. Reviewed

Senda T, Dogra P, Granot T, Furuhashi K, Snyder ME, Carpenter DJ, Szabo PA, Thapa P, Miron M, Farber DL

Mucosal immunology Vol. 12 ( 2 ) page： 378 - 389 2019.3

Neutrophil Fc gamma RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases Reviewed

Hiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark J. Miller, Yunfeng Chen, Florencia Rosetti, Samantha L. Hamilton, Lihua Yang, Spencer P. Pittman, Jiexi Liao, Jan M. Herter, Jeffrey C. Berry, Daniel J. DeAngelo, Cheng Zhu, George C. Tsokos, Tanya N. Mayadas

JOURNAL OF CLINICAL INVESTIGATION Vol. 127 ( 10 ) page： 3810 - 3826 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc gamma RIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc gamma RIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc gamma RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc gamma RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc gamma RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.

DOI： 10.1172/JCI94039

Serum-Starved Adipose-Derived Stromal Cells Ameliorate Crescentic GN by Promoting Immunoregulatory Macrophages Reviewed

Furuhashi K, Tsuboi N, Shimizu A, Katsuno T, Kim H, Saka Y, Ozaki T, Sado Y, Imai E, Matsuo S, Maruyama S.

Journal of the American Society of nephrology Vol. 24 page： 587-603 2013.3

Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase International journal

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

Language：English Publishing type：Research paper (scientific journal)

High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.

DOI： 10.1016/j.jnutbio.2019.05.017

Adipose derived stromal cells cultured in a low serum medium, but not bone marrow derived stromal cells, impede xenoantibody production. Reviewed

5. Saka Y, Furuhashi K, Katsuno T, Kim H, Ozaki T, Iwasaki K, Haneda M, Sato W, Tsuboi N, Ito Y, Matsuo S, Kobayashi T, Maruyama S.

Xenotransplantation Vol. 18 page： 196-208 2011.6

Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network. Reviewed International journal

Yuko Shimamura, Kazuhiro Furuhashi, Akihito Tanaka, Munetoshi Karasawa, Tomoya Nozaki, Shintaro Komatsu, Kenshi Watanabe, Asuka Shimizu, Shun Minatoguchi, Makoto Matsuyama, Yuriko Sawa, Naotake Tsuboi, Takuji Ishimoto, Hiroshi I Suzuki, Shoichi Maruyama

Communications biology Vol. 5 ( 1 ) page： 753 - 753 2022.7

Language：English Publishing type：Research paper (scientific journal)

Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

DOI： 10.1038/s42003-022-03712-2

In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney Reviewed

Tsuboi, T; Hattori, K; Ishimoto, T; Imai, K; Doke, T; Hagita, J; Ariyoshi, J; Furuhashi, K; Kato, N; Ito, Y; Kamiya, Y; Asanuma, H; Maruyama, S

MOLECULAR THERAPY NUCLEIC ACIDS Vol. 36 ( 1 ) page： 102387 2025.3

Urinary presepsin is a novel biomarker capable of directly assessing monocyte/macrophage infiltration in kidney diseases Reviewed

Niwa, S; Tanaka, A; Furuhashi, K; Hattori, K; Onogi, C; Sunohara, K; Owaki, A; Kato, A; Kawazoe, T; Watanabe, Y; Koshi-Ito, E; Kato, N; Kosugi, T; Maruyama, S

SCIENTIFIC REPORTS Vol. 14 ( 1 ) page： 30088 2024.12

Association between alpha blocker use and the risk of fractures in patients with chronic kidney disease: a cohort study Reviewed

Sunohara, K; Onogi, C; Tanaka, A; Furuhashi, K; Matsumoto, J; Hattori, K; Owaki, A; Kato, A; Kawazoe, T; Watanabe, Y; Koshi-Ito, E; Maruyama, S

BMC NEPHROLOGY Vol. 25 ( 1 ) page： 442 2024.12

A case of non-traumatic rectus sheath hematoma in a post-kidney transplant patient undergoing catheter embolization during anticoagulation treatment for atrial fibrillation Reviewed

Fujieda, K; Saito, S; Tanaka, A; Furuhashi, K; Ozeki, T; Yasuda, Y; Sano, Y; Ishida, S; Maruyama, S

CEN CASE REPORTS Vol. 13 ( 6 ) page： 528 - 533 2024.12

Language：English Publisher：CEN Case Reports

A 65-year-old man, a post living donor kidney transplant patient, was admitted to the intensive care unit (ICU) with a severe bacterial infection. He also tested positive for coronavirus disease and had a cough. On admission, heparin was administered for atrial fibrillation. On the third day of hospitalization, his general condition had recovered, and he was discharged from the ICU to the general ward. On the fourth day of hospitalization, he experienced abdominal pain, and a hard mass was palpated in the left lower abdomen. On the fifth day of hospitalization, contrast-enhanced computed tomography showed an extensive rectus sheath hematoma (RSH) extending from the left lower abdominal wall to the left side of the bladder, with extravasation from a small branch of the left inferior epigastric artery. Heparin was discontinued, and transcatheter arterial embolization was performed to control the bleeding. RSH is a rare disease, and cases of extensive hematoma in post-kidney transplant patients occur even less frequently. Patients taking anticoagulants and those with chronic kidney disease are at high risk for RSH, so physicians should be cognizant of this disease when these patients develop abdominal pain.

DOI： 10.1007/s13730-024-00890-2

Safety and Tolerability of ADR-001 Therapy for Immunoglobulin A Nephropathy. Reviewed International journal

Akihito Tanaka, Kazuhiro Furuhashi, Kumiko Fujieda, Asuka Horinouchi, Kayaho Maeda, Shoji Saito, Tetsushi Mimura, Yosuke Saka, Tomohiko Naruse, Takuji Ishimoto, Noritoshi Kato, Tomoki Kosugi, Fumie Kinoshita, Yachiyo Kuwatsuka, Yasuhiro Nakai, Shoichi Maruyama

Kidney360 Vol. 5 ( 11 ) page： 1692 - 1705 2024.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Immunoglobulin A nephropathy often requires kidney replacement therapy because of its refractoriness and because corticosteroids pose infection risks. However, mesenchymal stem cells offer clinical benefits because of their regenerative and immunomodulatory properties. This prospective clinical trial assessed the safety and tolerability of adipose-derived mesenchymal stem cell therapy and evaluated its therapeutic efficacy. METHODS: This phase 1 study included adult patients with refractory immunoglobulin A nephropathy that was difficult to treat with traditional therapies. Adipose-derived mesenchymal stem cell therapy comprising one intravenous dose of 1 × 108 cells was administered to three to six patients in cohort 1. The same intravenous dose was administered twice with a 2-week interval to six patients in cohort 2. Heparin was administered simultaneously. This study continued for 52 weeks, and the primary endpoints were safety and tolerability during the 6-week period after treatment administration. Secondary endpoints included adverse events and efficacy measures such as clinical remission, partial remission, urine protein remission, hematuria remission, time to remission, changes in the urine protein and hematuria levels, and changes in the estimated glomerular filtration rate. RESULTS: The three patients in cohort 1 and six patients in cohort 2 who received adipose-derived mesenchymal stem cell therapy achieved the primary endpoints. No severe adverse clinical events were observed. Therefore, the safety and tolerability of adipose-derived mesenchymal stem cells were confirmed. Improvements such as significantly decreased kidney damage markers and urinary protein levels were observed immediately after adipose-derived mesenchymal stem cell administration. CONCLUSIONS: The safety and tolerability of adipose-derived mesenchymal stem cells are acceptable for patients with immunoglobulin A nephropathy. TRIAL REGISTRATION: This trial was registered with the Japan Registry of Clinical Trials (jRCT2043200002; registration date: April 14, 2020) and ClinicalTrials.gov (NCT04342325; registration date: April 13, 2020).

DOI： 10.34067/KID.0000000000000563

Meflin/ISLR is a marker of adipose stem and progenitor cells in mice and humans that suppresses white adipose tissue remodeling and fibrosis Reviewed

Ishihara, T; Kato, K; Matsumoto, K; Tanaka, M; Hara, A; Shiraki, Y; Morisaki, H; Urano, Y; Ando, R; Ito, K; Mii, S; Esaki, N; Furuhashi, K; Takefuji, M; Suganami, T; Murohara, T; Enomoto, A

GENES TO CELLS Vol. 29 ( 10 ) page： 902 - 920 2024.10

Language：English Publisher：Genes to Cells

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα-positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue-resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage-tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high-fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown-like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction.

DOI： 10.1111/gtc.13154

A case of late-onset organizing pneumonia following COVID-19 infection in a post-kidney transplant patient Reviewed

Fujieda, K; Saito, S; Tanaka, A; Furuhashi, K; Yasuda, Y; Sano, Y; Kato, M; Maruyama, S

CEN CASE REPORTS Vol. 13 ( 5 ) page： 346 - 350 2024.10

Language：English Publisher：CEN Case Reports

A 50-year-old man who had undergone a living-donor kidney transplant 12 years prior for chronic renal failure due to autosomal dominant polycystic kidney disease contracted coronavirus disease 19 (COVID-19). He had a positive antigen test, mild symptoms, sore throat, and fever of 37.9 ℃. The patient was treated with molnupiravir for 5 days, and the symptoms disappeared 5 days after onset. However, 10 days after onset, he developed a fever of approximately 37 ℃ and a non-productive cough; 27 days after onset, the patient was hospitalized for anorexia and a worsening respiratory condition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test results on admission were negative, and no antiviral medications were administered against SARS-CoV-2. Computed tomography revealed extensive ground-glass opacities in both lung fields. The patient was treated with steroid pulse therapy, ceftriaxone, atovaquone, azithromycin, and respiratory management using a high-flow nasal cannula. The combined therapies were successful, and the patient was managed with a nasal oxygen cannula after 3 days. Oxygen administration was discontinued after 6 days of hospitalization, and the patient was discharged after 14 days. Based on the laboratory findings, bacterial, interstitial, and Pneumocystis pneumonia were unlikely. The success of the steroid pulse therapy suggested that respiratory failure was caused by pneumonia due to the immune response after COVID-19 infection.

DOI： 10.1007/s13730-023-00849-9

MPO-ANCA-positive rapidly progressive glomerulonephritis after COVID-19 vaccination during treatment of plaque psoriasis with bimekizumab Reviewed

Takuya Sugiura, Tomohito Doke, Akihito Tanaka, Yuka Sato, Kayaho Maeda, Kazuhiro Furuhashi, Noritoshi Kato, Tomoki Kosugi, Shoichi Maruyama

2024.9

Changes in antibody titer after four and five doses of the SARS-CoV-2 vaccine in Japanese post-kidney transplant patients Reviewed

Fujieda, K; Tanaka, A; Kikuchi, R; Takai, N; Saito, S; Yasuda, Y; Sano, Y; Kato, M; Furuhashi, K; Maruyama, S

THERAPEUTIC APHERESIS AND DIALYSIS Vol. 28 ( 4 ) page： 489 - 498 2024.8

Language：English Publisher：Therapeutic Apheresis and Dialysis

Introduction: Immunosuppressed patients exhibit low antibody acquisition rates following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Kidney transplant recipients previously exhibited low antibody acquisition rates after two vaccine doses, which increased after the third dose. We evaluated antibody titers of Japanese post-kidney transplant patients after the fourth and fifth vaccinations. Methods: Antibody titers for SARS-CoV-2 spike protein were measured between 3 weeks and 3 months after the fourth or fifth vaccination. Results: Increased antibody acquisition rates were observed after the fourth (75.0% antibody-positive) and fifth (81.5% antibody-positive) vaccinations. The antibody-acquired group after the fourth vaccination exhibited a higher body mass index and estimated glomerular filtration rate (eGFR) than the non-acquired group. A higher eGFR was associated with antibody acquisition after the fifth vaccination. Conclusion: In Japanese post-kidney transplant patients, the antibody acquisition rate increased with each vaccine additional dose. Additional vaccinations are recommended to protect against SARS-CoV-2 infection.

DOI： 10.1111/1744-9987.14114