Faculty Profiles - MAEDA Kayaho

Pyruvate dehydrogenase phosphatase catalytic subunit 2 limits Th17 differentiation. International journal

Kono M., Yoshida N., Maeda K., Skinner NE, Pan W., Kyttaris VC, Tsokos MG, Tsokos GC

Proceedings of the National Academy of Sciences of the United States of America Vol. 115 ( 37 ) page： 9288-9293 2018.9

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. International journal

Kayaho Maeda, Kotaro Otomo, Nobuya Yoshida, Mones S Abu-Asab, Kunihiro Ichinose, Tomoya Nishino, Michihito Kono, Andrew Ferretti, Rhea Bhargava, Shoichi Maruyama, Sean Bickerton, Tarek M Fahmy, Maria G Tsokos, George C Tsokos

The Journal of clinical investigation Vol. 128 ( 8 ) page： 3445 - 3459 2018.8

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

Podocyte malfunction occurs in autoimmune and nonautoimmune kidney disease. Calcium signaling is essential for podocyte injury, but the role of Ca2+/calmodulin-dependent kinase (CaMK) signaling in podocytes has not been fully explored. We report that podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and lupus-prone and lipopolysaccharide- or adriamycin-treated mice display increased expression of CaMK IV (CaMK4), but not CaMK2. Mechanistically, CaMK4 modulated podocyte motility by altering the expression of the GTPases Rac1 and RhoA and suppressed the expression of nephrin, synaptopodin, and actin fibers in podocytes. In addition, it phosphorylated the scaffold protein 14-3-3β, which resulted in the release and degradation of synaptopodin. Targeted delivery of a CaMK4 inhibitor to podocytes preserved their ultrastructure, averted immune complex deposition and crescent formation, and suppressed proteinuria in lupus-prone mice and proteinuria in mice exposed to lipopolysaccharide-induced podocyte injury by preserving nephrin/synaptopodin expression. In animals exposed to adriamycin, podocyte-specific delivery of a CaMK4 inhibitor prevented and reversed podocyte injury and renal disease. We conclude that CaMK4 is pivotal in immune and nonimmune podocyte injury and that its targeted cell-specific inhibition preserves podocyte structure and function and should have therapeutic value in lupus nephritis and podocytopathies, including focal segmental glomerulosclerosis.

DOI： 10.1172/JCI99507

The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases Reviewed

Yoshiko Mori, Tomohiro Masuda, Tomoki Kosugi, Tomoki Yoshioka, Mayuko Hori, Hiroshi Nagaya, Kayaho Maeda, Yuka Sato, Hiroshi Kojima, Noritoshi Kato, Takuji Ishimoto, Takayuki Katsuno, Yukio Yuzawa, Kenji Kadomatsu, Shoichi Maruyama

Clinical and Experimental Nephrology Vol. 22 ( 4 ) page： 815 - 824 2018.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Background: Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease. Methods: Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch–Schönlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system. Results: In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients. Conclusion: Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases.

DOI： 10.1007/s10157-017-1518-2

Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. International journal

Kono M., Yoshida N., Maeda K., Tsokos GC

Proceedings of the National Academy of Sciences of the United States of America Vol. 115 ( 10 ) page： 2478-2483 2018.3

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis Reviewed International journal

Tomohiro Masuda, Kayaho Maeda, Waichi Sato, Tomoki Kosugi, Yuka Sato, Hiroshi Kojima, Noritoshi Kato, Takuji Ishimoto, Naotake Tsuboi, Kenji Uchimura, Yukio Yuzawa, Shoichi Maruyama, Kenji Kadomatsu

AMERICAN JOURNAL OF PATHOLOGY Vol. 187 ( 4 ) page： 740 - 751 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including Lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (MdK+/+) mice showed more severe glomerular injury than MK-deficient (Mdk(-/-)) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk(-/-) mice, the frequency of splenic CD69(+) T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk(+/+) mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4(+) T cells in vivo and in vitro. MK induced activated CD4(+) T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4(+) T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4(+) T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

DOI： 10.1016/j.ajpath.2016.12.006

CD147/BSG ACCELERATES TUBULOINTERSTITIAL INJURY AND LIVER DYSFUNCTION IN HIGH-FAT DIET Reviewed

Yoshiko Mori, Tomoki Kosugi, Tomoki Yoshioka, Takahiro Hayasaki, Kayaho Maeda, Noritoshi Kato, Takuji Ishimoto, Seiichi Matsuo, Shoichi Maruyama

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 31 page： 371 - 372 2016.5

THE ROLE OF BASIGIN IN THE DEVELOPMENT OF PROTEINURIA Reviewed

Tomoki Yoshioka, Tomoki Kosugi, Yoshiko Mori, Kayaho Maeda, Seiichi Matsuo, Shoichi Maruyama

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 31 page： 103 - 103 2016.5

Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids Reviewed International journal

Yuka Sato, Waichi Sato, Shoichi Maruyama, Christopher S. Wilcox, John R. Falck, Tomohiro Masuda, Tomoki Kosugi, Hiroshi Kojima, Kayaho Maeda, Kazuhiro Furuhashi, Masahiko Ando, Enyu Imai, Seiichi Matsuo, Kenji Kadomatsu

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Vol. 26 ( 8 ) page： 1806 - 15 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC NEPHROLOGY

The effects of endothelium-derived hyperpolarizing factors have been attributed to cytochrome P450-derived epoxyeicosatrienoic acids (EETs), but the regulation and role of EETs in endothelial dysfunction remain largely unexplored. Hypertension is a primary risk factor for renal dysfunction, which is frequently accompanied by various systemic diseases induced by endothelial dysfunction in the microcirculation. We previously reported that the endothelial growth factor midkine (MK) enhances hypertension in a model of CKD. Here, we investigated the hypothesis that MK regulates EET activity and thereby BP. MK gene-deleted mice were resistant to hypertension and developed less glomerulosclerosis and proteinuria after administration of a nitric oxide synthase (NOS) inhibitor in the setting of uninephrectomy. The hypertension observed in uninephrectomized wild-type mice after NOS inhibition was ameliorated by anti-MK antibody. MK-deficient mice produced higher amounts of EETs, and EETs dominantly regulated BP in these mice. Furthermore, MK administration to MK-deficient mice recapitulated the BP control observed in wild-type mice. EETs also dominantly regulated renal blood flow, which may influence renal function, in MK-deficient mice. Taken together, these results suggest that the MK/EET pathway is physiologically engaged in BP control and could be a target for the treatment of hypertension complicated by endothelial dysfunction.

DOI： 10.1681/ASN.2013121259

CD147 (EMMPRIN/Basigin) in kidney diseases: From an inflammation and immune system viewpoint Reviewed

Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu

Nephrology Dialysis Transplantation Vol. 30 ( 7 ) page： 1097 - 103 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

The glycosylated transmembrane protein CD147/basigin, also known as extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN), contributes to cell survival, migration and cancer invasion. In normal kidneys, high expression of CD147 is detected only in the basolateral side of tubular epithelial cells (TECs). The pathophysiological roles of CD147 in the kidneys are diverse, ranging from involvement in the occurrence of acute kidney injury (AKI) that is frequently accompanied by ischemia, inflammation and a loss of self-tolerance to the progression of chronic kidney disease (CKD) that is caused by an imbalance in extracellular matrix protein turnover. In AKI induced by ischemia, it is the CD147 on neutrophils, rather than that on TECs, that coordinately participates in massive neutrophil recruitment via acting as a physiological ligand for E-selectin, which is specifically enhanced in the endothelium upon inflammatory stimulation. In the CKD that follows AKI, a molecular circuit involving CD147, MMPs and transforming growth factor-β may be involved in the pathogenesis of progressive fibrosis through hyaluronan production and macrophage infiltration. Whereas CD147 thus plays deleterious roles in ischemic and fibrotic kidney injuries, CD147 expression on lymphocytes might decrease the disease activity of lupus nephritis (LN) by functioning as a potential negative regulator of the extraordinary proliferation of lymphocytes that occurs in this disease. In line with these basic studies, our clinical data indicate the potential of plasma CD147 to function as a critical biomarker for both ischemic AKI and LN. CD147 is also involved in crosstalk between the kidneys and distant organs, which may be mediated by chemotactic cytokines that are derived from circulating inflammatory cells and damaged organs. Disruption of such a vicious chain reaction involving CD147 would therefore be required in order to overcome kidney diseases. Multidisciplinary research regarding CD147 functions may open a new avenue for targeting therapeutics for kidney diseases.

DOI： 10.1093/ndt/gfu302

CD147/Basigin Limits Lupus Nephritis and Th17 Cell Differentiation in Mice by Inhibiting the Interleukin-6/STAT-3 Pathway Reviewed International journal

Kayaho Maeda, Tomoki Kosugi, Waichi Sato, Hiroshi Kojima, Yuka Sato, Daisuke Kamimura, Noritoshi Kato, Naotake Tsuboi, Yukio Yuzawa, Seiichi Matsuo, Masaaki Murakami, Shoichi Maruyama, Kenji Kadomatsu

ARTHRITIS & RHEUMATOLOGY Vol. 67 ( 8 ) page： 2185 - 95 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Objective. Interleukin-17 (IL-17)-producing T cells (Th17 cells) play critical roles in the pathogenesis of immune-related diseases, including systemic lupus erythematosus. However, the fundamental mechanism regulating Th17 cell differentiation is not fully understood. Recently, we demonstrated that plasma levels of CD147/basigin (Bsg) in patients with lupus nephritis (LN) were closely associated with disease activity. but the molecular mechanism involving Bsg has been elusive. Here, we addressed the role of Bsg in the pathogenesis of LN.
Methods. Injections of pristane (2,6,10,14-tetramethylpentadecane [TMPD]) were administered to Bsg(-/-) or Bsg(+/+) mice to induce LN. The mice were killed 6 months after being injected, for histologic and biochemical analyses of the kidneys and spleens.
Results. Pristane induced LN more strikingly in Bsg(-/-) mice than in Bsg(+/+) mice, even though humoral autoimmunity was similarly increased in both genotypes. The increased number of Th17, but not Th1, Treg cells, was augmented in Bsg(-/-) mice. The expression of IL-17 was also increased in the kidneys of Bsg(-/-) mice, in proportion to LN disease activity. Furthermore, treatment with anti-IL-17 antibody reduced LN disease activity in Bsg(-/-) mice. Complementary to these phenotypes of Bsg(-/-) mice, Bsg expression was enhanced in activated CD4+ T cells in vivo and in vitro. Bsg deficiency selectively augmented in vitro differentiation of naive CD4+ T cells to Th17 cells and STAT-3 phosphorylation during this differentiation. Moreover, STAT-3 phosphorylation was suppressed by crosslinking of Bsg with its antibody.
Conclusion. Bsg plays an indispensable role in Th17 cell differentiation as a negative regulator by suppressing the IL-6/STAT-3 pathway.

DOI： 10.1002/art.39155

Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency Reviewed

Yiqin Shi, Naotake Tsuboi, Kazuhiro Furuhashi, Qiuna Du, Asuka Horinouchi, Kayaho Maeda, Tomoki Kosugi, Seiichi Matsuo, Shoichi Maruyama

JOURNAL OF IMMUNOLOGY Vol. 193 ( 10 ) page： 5129 - 39 2014.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Diffuse pulmonary hemorrhage (DPH) is an uncommon but critical complication of systemic lupus erythematosus. Peritoneal administration of 2,6,10,14-tetramethylpentadecane (pristane) can recapitulate a lupus-like syndrome in mice, which can develop into DPH within a few weeks, especially in C57BL/6 mice. Mac-1 (CD11b/CD18), a leukocyte adhesion molecule, is known to play a role in inflammation by regulating migration of leukocytes into injured tissue. In this study, we aimed to clarify the role of Mac-1 in pristane-induced DPH, using Mac-1(-/-) and wild-type (WT) mice on a C57BL/6 background. After pristane injection, Mac-1(-/-) mice showed reduced prevalence of DPH and attenuated peritonitis compared with WT mice. Analysis of the peritoneal lavage on days 5 and 10 after pristane treatment revealed increased numbers of eosinophils and alternatively activated macrophages, but decreased numbers of neutrophils and classically activated macrophages in Mac-1(-/-) mice compared with WT. Enhanced production of IL-4 and IL-13, both key mediators of macrophage polarization toward the mannose receptor(+) (MMR+) phenotype, was observed in the peritoneal cavity of Mac-1(-/-) mice. Depletion of neutrophils and eosinophils or adoptive transfer of classically activated macrophages resulted in the exacerbation of pristane-mediated DPH in both WT and Mac-1(-/-) mice. Moreover, peritoneal transfer of F4/80(high)MMR(+) alternatively activated macrophages successfully reduced the prevalence of DPH in WT mice. Collectively, Mac-1 promoted acute inflammatory responses in the peritoneal cavity and the lungs by downregulating granulocyte migration and subsequent phenotypic conversion of macrophages in a pristane-induced systemic lupus erythematosus model.

DOI： 10.4049/jimmunol.1401051

CD147/basigin reflects renal dysfunction in patients with acute kidney injury Reviewed

Hiroshi Nagaya, Tomoki Kosugi, Mayuko Maeda-Hori, Kayaho Maeda, Yuka Sato, Hiroshi Kojima, Hiroki Hayashi, Noritoshi Kato, Takuji Ishimoto, Waichi Sato, Yukio Yuzawa, Seiichi Matsuo, Kenji Kadomatsu, Shoichi Maruyama

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 18 ( 5 ) page： 746 - 54 2014.10

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

Acute tubular necrosis (ATN) describes a form of intrinsic acute kidney injury (AKI) that results from persistent hypoperfusion and subsequent activation of the immune system. A glycosylated transmembrane protein, CD147/basigin, is involved in the pathogenesis of renal ischemia and fibrosis. The present study investigated whether CD147 can reflect pathological features and renal dysfunction in patients with AKI.
Plasma and spot urine samples were collected from 24 patients (12 controls and 12 with ATN) who underwent renal biopsy between 2008 and 2012. In another study, patients undergoing open surgery to treat abdominal aortic aneurysms (AAAs) were enrolled in 2004. We collected urine and plasma samples from seven patients with AKI and 33 patients without AKI, respectively. In these experiments, plasma and urinary CD147, and urinary l-fatty acid-binding protein (l-FABP) levels were measured, and the former expression in kidneys was examined by immunostaining.
In biopsy tissues of ATN with severe histological features, CD147 induction was strikingly present in inflammatory cells such as macrophages and lymphocytes in the injured interstitium, but not in damaged tubules representing atrophy. Both plasma and urinary CD147 levels were strikingly increased in ATN patients; both values showed greater correlations with renal dysfunction compared to urinary l-FABP. In patients who had undergone open AAA surgery, urinary and plasma CD147 values in AKI patients were significantly higher than in non-AKI patients at post-operative day 1, similar to the profile of urinary l-FABP.
CD147 was prominent in its ability to detect AKI and may allow the start of preemptive medication.

DOI： 10.1007/s10157-013-0916-3

Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis Reviewed International journal

Hiroshi Kojima, Tomoki Kosugi, Waichi Sato, Yuka Sato, Kayaho Maeda, Noritoshi Kato, Kiyonari Kato, Shinichiro Inaba, Takuji Ishimoto, Naotake Tsuboi, Seiichi Matsuo, Shoichi Maruyama, Yukio Yuzawa, Kenji Kadomatsu

American Journal of Pathology Vol. 182 ( 2 ) page： 410 - 9 2013.2

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

Inflammatory cell infiltration and fibrin deposition play important roles in the development of crescentic glomerulonephritis (GN). In particular, activation of coagulation is an indispensable factor in crescent formation. However, the mechanisms underlying the pathogenesis of crescent formation have not been completely elucidated. We identified the growth factor midkine (MK) as a novel key molecule in the progression of crescentic GN induced by anti-glomerular basement membrane antibody. Despite the lack of significant differences in autologous and heterologous reactions, MK-deficient (Mdk -/-) mice unexpectedly showed a greater number of necrotizing glomerular injuries than wild-type (Mdk+/+) mice. Likewise, more tubulointerstitial damage was observed in Mdk-/- mice, and this damage positively correlated with glomerular injury. Plasminogen activator inhibitor (PAI)-1 was strongly induced in the injured glomerulus of Mdk -/- mice, particularly in crescents and endothelial cells. This enhanced PAI-1 production was associated with an increase in inflammatory cell infiltration and matrix deposition in the glomerulus and the interstitium of Mdk-/- mice. In line with these in vivo data, primary cultured endothelial cells derived from Mdk-/- mice exhibited higher PAI-1 mRNA expression on fibrin challenge and less fibrinolysis than Mdk+/+ mice. In contrast, the expression of plasminogen activators was not affected. Our combined data suggest that MK leads to a blockade of PAI-1, which is closely associated with the suppression of crescentic GN. © 2013 American Society for Investigative Pathology.

DOI： 10.1016/j.ajpath.2012.10.016

Myoclonus after dextromethorphan administration in peritoneal dialysis Reviewed

Akio Tanaka, Tadashi Nagamatsu, Makoto Yamaguchi, Atsushi Nomura, Fumiko Nagura, Kayaho Maeda, Tatsuhito Tomino, Tatsuhito Watanabe, Hideaki Shimizu, Yoshiro Fujita, Yasuhiko Ito

Annals of Pharmacotherapy Vol. 45 ( 1 ) page： e1 2011.1

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

To report a case of myoclonus that developed after administration of dextromethorphan. CASE SUMMARY: A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. DISCUSSION: As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 *1/*10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. CONCLUSIONS: Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.

DOI： 10.1345/aph.1P301