2021/10/20 更新

写真a

カセダ　リョウヘイ
忰田　亮平
KASEDA Ryohei
所属
医歯学総合病院 腎・膠原病内科 助教
職名
助教
外部リンク

学位

  • 医学博士 （ 2008年3月   新潟大学 ）

研究キーワード

  • MRI

  • HDL

  • 腎臓

研究分野

  • ライフサイエンス / 腎臓内科学

経歴（researchmap）

  • 新潟大学医歯学総合病院 腎・膠原病内科 助教   Nephrology and Rheumatology, Medical and Dental Hospital

    2016年5月 - 現在

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  • 新潟大学大学院医歯学総合研究科 病態栄養学講座 特任助教   Graduate School of Medical and Dental Sciences

    2014年4月 - 2016年4月

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  • 米国バンダービルト大学小児科 リサーチフェローとして留学

    2011年4月 - 2014年3月

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  • 新潟大学大学院医歯学総合研究科 腎・膠原病内科関連病院にて勤務

    2008年4月 - 2011年3月

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  • 新潟大学第二内科関連病院にて勤務

    2003年4月 - 2004年3月

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  • 研修医として臨床研修

    2001年4月 - 2003年3月

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▶ 全件表示

経歴

  • 新潟大学   医歯学総合病院　腎・膠原病内科   助教

    2016年5月 - 現在

  • 新潟大学   医歯学総合研究科   特任助教

    2014年4月 - 2016年4月

学歴

  • 新潟大学大学院医歯学総合研究科 博士課程

    2004年4月 - 2008年3月

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  • 新潟大学医学部医学科

    1995年4月 - 2001年3月

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所属学協会

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留学歴

  • バンダービルト大学　   リサーチフェロー

    2011年4月 - 2014年3月

 

論文

  • Rice Endosperm Protein Administration to Juvenile Mice Regulates Gut Microbiota and Suppresses the Development of High-Fat Diet-Induced Obesity and Related Disorders in Adulthood. 査読 国際誌

    Yuki Higuchi, Michihiro Hosojima, Hideyuki Kabasawa, Shoji Kuwahara, Sawako Goto, Koji Toba, Ryohei Kaseda, Takahiro Tanaka, Nobutaka Kitamura, Hayato Takihara, Shujiro Okuda, Masayuki Taniguchi, Hitoshi Arao, Ichiei Narita, Akihiko Saito

    Nutrients   11 ( 12 )   2019年12月

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    記述言語：英語  

    Obesity and related disorders, which are increasing in adults worldwide, are closely linked to childhood diet and are associated with chronic inflammation. Rice endosperm protein (REP) intake during adulthood has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. However, the effects of REP intake during childhood on adulthood health are unclear. Therefore, we used a mouse model to experimentally investigate the preconditioning effects of REP intake during childhood on the development of obesity and related disorders in adulthood. Male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP during the juvenile period and then a high-fat diet (HFD) containing casein or REP during adulthood. Mice fed REP during the juvenile period showed better body weight, blood pressure, serum lipid profiles, lipopolysaccharide (LPS)-binding protein levels, and glucose tolerance in adulthood than those fed casein during the juvenile period. HFD-induced renal tubulo-glomerular alterations and hepatic microvesicular steatosis were less evident in REP-fed mice than in casein-fed ones. REP intake during the juvenile period improved HFD-induced dysbiosis (i.e., Escherichia genus proliferation and reduced gut microbiota diversity), thereby suppressing endotoxin-related chronic inflammation. Indeed, REP-derived peptides showed antibacterial activity against Escherichia coli, a major producer of LPS. In conclusion, REP supplementation during the juvenile period may regulate the gut microbiota and thus suppress the development of obesity and related disorders in adulthood in mice.

    DOI： 10.3390/nu11122919

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  • Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study. 査読 国際誌

    Satoshi Shoji, Michihiro Hosojima, Hideyuki Kabasawa, Rie Kondo, Satoru Miura, Satoshi Watanabe, Nobumasa Aoki, Ryohei Kaseda, Shoji Kuwahara, Naohito Tanabe, Yoshiaki Hirayama, Ichiei Narita, Toshiaki Kikuchi, Hiroshi Kagamu, Akihiko Saito

    BMC cancer   19 ( 1 )   1170 - 1170   2019年12月

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    記述言語：英語  

    BACKGROUND: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer. METHODS: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α1-microglobulin, β2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment. RESULTS: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline. CONCLUSIONS: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.

    DOI： 10.1186/s12885-019-6398-2

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  • Higher estimated net endogenous acid production with lower intake of fruits and vegetables based on a dietary survey is associated with the progression of chronic kidney disease. 査読 国際誌

    Koji Toba, Michihiro Hosojima, Hideyuki Kabasawa, Shoji Kuwahara, Toshiko Murayama, Keiko Yamamoto-Kabasawa, Ryohei Kaseda, Eri Wada, Reiko Watanabe, Naohito Tanabe, Yoshiki Suzuki, Ichiei Narita, Akihiko Saito

    BMC nephrology   20 ( 1 )   421 - 421   2019年11月

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    記述言語：英語  

    BACKGROUND: Dietary acid load has been suggested to mediate the progression of chronic kidney disease (CKD). However, it is unclear what kinds of foods are actually associated with dietary acid load in patients with CKD. The self-administered diet history questionnaire (DHQ), which semi-quantitatively assesses the dietary habits of Japanese individuals through 150 question items, can estimate average daily intake of various foods and nutrients during the previous month. Using the DHQ, we investigated the association of dietary acid load with CKD progression. We also analyzed the kinds of food that significantly affect dietary acid load. METHODS: Subjects were 96 outpatients with CKD (average estimated glomerular filtration rate [eGFR], 53.0 ± 18.1 ml/min/1.73 m2) at Niigata University Hospital, who had completed the DHQ in 2011. We calculated net endogenous acid production (NEAP) from potassium and protein intake evaluated by the DHQ in order to assess dietary acid load. CKD progression was assessed by comparing eGFR between 2008 and 2014. RESULTS: NEAP was not correlated with protein intake (r = 0.088, p = 0.398), but was negatively correlated with potassium intake (r = - 0.748, p < 0.001). Reduction in eGFR from 2008 to 2014 was estimated to be significantly greater in patients with higher NEAP (NEAP > 50.1 mEq/day, n = 45) than in those with lower NEAP (NEAP ≤50.1 mEq/day, n = 50) by 5.9 (95% confidence interval [95%CI], 0.1 to 11.6) ml/min/1.73 m2. According to multiple logistic regression analysis, higher NEAP was significantly associated with lower intake of fruits (odds ratio [OR], 6.454; 95%CI, 2.19 to 19.00), green and yellow vegetables (OR, 5.18; 95%CI, 1.83 to14.66), and other vegetables (OR, 3.87; 95%CI, 1.29 to 11.62). CONCLUSIONS: Elevated NEAP could be a risk factor for CKD progression. Low intake of fruits and vegetables would increase dietary acid load and might affect the progression of renal dysfunction in Japanese CKD patients.

    DOI： 10.1186/s12882-019-1591-8

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  • Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis. 査読

    Kaseda R, Tsuchida Y, Gamboa JL, Zhong J, Zhang L, Yang H, Dikalova A, Bian A, Davies S, Fogo AF, Linton MF, Brown NJ, Ikizler TA, Kon V

    Nutrition, metabolism, and cardiovascular diseases : NMCD   28 ( 6 )   582 - 591   2018年6月

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  • Kidney morphological parameters measured using noncontrast-enhanced steady-state free precession MRI with spatially selective inversion recovery pulse correlate with eGFR in patients with advanced CKD 査読

    Tadashi Otsuka, Yoshikatsu Kaneko, Yuya Sato, Ryohei Kaseda, Ryuji Aoyagi, Suguru Yamamoto, Shin Goto, Ichiei Narita

    Clinical and Experimental Nephrology   22 ( 1 )   45 - 54   2018年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

    Background: It is well known that atrophic renal changes are associated with chronic kidney disease (CKD) progression, but conventional diagnostic imaging methods such as noncontrast-enhanced computed tomography and magnetic resonance imaging (MRI) have been insufficient for precisely assessing kidney function because they cannot clearly distinguish between the medulla and cortex. Hence, here we used noncontrast-enhanced steady-state free precession (SSFP) MRI with a spatially selective inversion recovery (IR) pulse to improve visibility for renal corticomedullary differentiation and evaluated the association between morphological parameters and kidney function in patients with CKD. Methods: Kidney corticomedullary contrast ratio, cortical and medullary areas, and minimal cortical thickness of 107 patients with CKD G1–G5 were measured using SSFP MRI with a spatially selective IR pulse and the association between these morphological parameters and kidney function were evaluated. Results: Corticomedullary contrast ratio was significantly improved on SSFP MRI compared with conventional in-phase T1-weighted gradient-echo MRI and positively correlated with estimated glomerular filtration ratio (eGFR), raw eGFR, and 24-h creatinine clearance. The medullary and cortical areas and minimal cortical thickness also positively correlated with those of kidney functional markers and the age. In patients with CKD and diabetes mellitus (DM), the correlation coefficients between raw eGFR and morphological parameters were higher than those in patients without DM, while minimal cortical thickness was larger in CKD patients with DM with a raw eGFR ≥ 45 mL/min. Conclusion: Kidney morphological parameters measured with SSFP MRI were clearly correlated with kidney function in patients with CKD, including those with advanced kidney dysfunction.

    DOI： 10.1007/s10157-017-1413-x

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  • Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism. 査読

    Kaseda R, Tsuchida Y, Yang HC, Yancey PG, Zhong J, Tao H, Bian A, Fogo AB, Linton MRF, Fazio S, Ikizler TA, Kon V

    BMC nephrology   19 ( 1 )   17   2018年1月

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  • A Randomized, Double-Blind, Crossover Pilot Trial of Rice Endosperm Protein Supplementation in Maintenance Hemodialysis Patients 査読

    Michihiro Hosojima, Hisaki Shimada, Yoshitsugu Obi, Shoji Kuwahara, Ryohei Kaseda, Hideyuki Kabasawa, Hazuki Kondo, Mikio Fujii, Reiko Watanabe, Yoshiki Suzuki, Motoni Kadowaki, Shigeru Miyazaki, Akihiko Saito

    SCIENTIFIC REPORTS   7 ( 1 )   18003   2017年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

    In maintenance hemodialysis (MHD) patients, low protein intake is associated with protein-energy wasting, a risk factor that affects outcome. However, increased protein intake may lead to hyperphosphatemia and hyperkalemia, which are also mortality risk factors. Here, we evaluated the safety and effects of purified rice endosperm protein (REP), which contains less phosphorus and potassium than soy and casein proteins, as a supplemental protein source for MHD patients. This randomized, double-blind, placebo-controlled, crossover pilot study of REP supplementation (5 g/day x 4 weeks) was carried out in 50 Japanese adult MHD patients (1 dropped out); the primary outcome was the change in the urea kinetic-based normalized protein catabolic rate (nPCR), an indicator of protein intake in MHD patients. Intention-to-treat analyses of 24 patients in the REP-first group and 25 in the placebo-first group showed that REP supplementation increased nPCR significantly by 0.07 g/kg/day (95% confidence interval, 0.03-0.11), whereas changes in serum phosphorus and potassium concentrations were not different from the placebo. REP supplementation did not show a significant effect on other nutritional or metabolic parameters and no specific complications. In conclusion, purified REP with efficient bioavailability may be safe and useful for dietary supplementation in MHD patients.

    DOI： 10.1038/s41598-017-18340-8

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  • Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity 査読

    Yoshihisa Hori, Nobumasa Aoki, Shoji Kuwahara, Michihiro Hosojima, Ryohei Kaseda, Sawako Goto, Tomomichi Iida, Shankhajit De, Hideyuki Kabasawa, Reika Kaneko, Hiroyuki Aoki, Yoshinari Tanabe, Hiroshi Kagamu, Ichiei Narita, Toshiaki Kikuchi, Akihiko Saito

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   28 ( 6 )   1783 - 1791   2017年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

    Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant Staphylococcus aureus, and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin in vitro, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated via megalin in the clinical setting.

    DOI： 10.1681/ASN.2016060606

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  • Exocytosis-Mediated Urinary Full-Length Megalin Excretion Is Linked With the Pathogenesis of Diabetic Nephropathy 査読

    Shankhajit De, Shoji Kuwahara, Michihiro Hosojima, Tomomi Ishikawa, Ryohei Kaseda, Piyali Sarkar, Yusuke Yoshioka, Hideyuki Kabasawa, Tomomichi Iida, Sawako Goto, Koji Toba, Yuki Higuchi, Yoshiki Suzuki, Masanori Hara, Hiroyuki Kurosawa, Ichiei Narita, Yoshiaki Hirayama, Takahiro Ochiya, Akihiko Saito

    DIABETES   66 ( 5 )   1391 - 1404   2017年5月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER DIABETES ASSOC  

    Efficient biomarkers for diabetic nephropathy (DN) have not been established. Using ELISA, we found previously that urinary levels of full-length megalin (C-megalin), a multiligand endocytic receptor in proximal tubules, was positively correlated with DN progression in patients with type 2 diabetes mellitus (T2DM). Here, we found that urinary extracellular vesicle (UEV) excretion and C-megalin content in UEVs or in their exosomal fraction increased along with the progression of the albuminuric stages in patients with T2DM. Cultured immortalized rat proximal tubule cells (IRPTCs) treated with fatty acid-free BSA or advanced glycation end product-modified BSA (AGE-BSA), endocytic ligands of megalin, increased EV excretion, and their C-megalin content. C-megalin excretion from IRPTCs via extracellular vesicles was significantly blocked by an exosome-specific inhibitor, GW4869, indicating that this excretion is mainly exocytosis-mediated. AGE-BSA treatment of IRPTCs caused apparent lysosomal dysfunction, which stimulated multivesicular body formation, resulting in increased exosomal C-megalin excretion. In a high-fat diet-induced, megalin-mediated kidney injury model in mice, urinary C-megalin excretion also increased via UEVs. Collectively, exocytosis-mediated urinary C-megalin excretion is associated with the development and progression of DN in patients with T2DM, particularly due to megalin-mediated lysosomal dysfunction in proximal tubules, and hence it could be a candidate biomarker linked with DN pathogenesis.

    DOI： 10.2337/db16-1031

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  • The Assessment of the Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Glucocorticoid-induced Diabetes by Continuous Glucose Monitoring 査読

    Yusuke Yata, Michihiro Hosojima, Hideyuki Kabasawa, Tomomi Ishikawa, Ryohei Kaseda, Noriaki Iino, Yoshiki Suzuki, Akihiko Saito, Ichiei Narita

    INTERNAL MEDICINE   56 ( 19 )   2555 - 2562   2017年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

    Objective The administration of glucocorticoids usually causes a mild increase in fasting glucose levels and a greater dose-dependent increase in postprandial values in patients without pre-existing diabetes mellitus. Patients with persistent hyperglycemia due to glucocorticoid therapy sometimes require insulin therapy, which might result in increased weight gain and more episodes of hypoglycemia, some of which are severe. On the other hand, scant evidence is available on the efficacy of oral hypoglycemic agents in treating glucocorticoid-induced diabetes. In this study, we evaluated the efficacy of dipeptidyl peptidase (DPP)-4 inhibitors in patients with glucocorticoid-induced diabetes by continuous glucose monitoring (CGM).
    Methods We examined the glycemic profiles using CGM at baseline and 1-4 weeks after initiating DPP-4 inhibitor treatment in patients with newly developed glucocorticoid-induced diabetes.
    Results Eleven patients who had been diagnosed with kidney disease or other diseases with renal involvement were recruited for the present retrospective study. After starting DPP-4 inhibitors, the mean and standard deviation (SD) of the glucose level, and the mean amplitude of glycemic excursion (MAGE) were significantly improved in comparison to baseline. Furthermore, the area over the curve (AOC) for the glucose levels &lt;70 mg/dL was not increased in comparison to baseline after the initiation of DPP-4 inhibitor treatment. The results indicate that the treatment of patients with glucocorticoid-induced diabetes using DPP-4 inhibitors can minimize the risk of hypoglycemia and reduce glucose variability.
    Conclusion DPP-4 inhibitors are potentially useful for blood glucose control in patients with glucocorticoid-induced diabetes.

    DOI： 10.2169/internalmedicine.8296-16

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  • Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease 査読

    Shoji Kuwahara, Michihiro Hosojima, Reika Kaneko, Hiroyuki Aoki, Daisuke Nakano, Taiji Sasagawa, Hideyuki Kabasawa, Ryohei Kaseda, Ryota Yasukawa, Tomomi Ishikawa, Akiyo Suzuki, Hiroyoshi Sato, Shun Kageyama, Takahiro Tanaka, Nobutaka Kitamura, Ichiei Narita, Masaaki Komatsu, Akira Nishiyama, Akihiko Saito

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   27 ( 7 )   1996 - 2008   2016年7月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

    Obesity, an important risk factor for metabolic syndrome (MetS) and cardiovascular disease, is often complicated by CKD, which further increases cardiovascular risk and causes ESRD. To elucidate the mechanism underlying this relationship, we investigated the role of the endocytic receptor megalin in proximal tubule epithelial cells (PTECs). We studied a high-fat diet (HFD)-induced obesity/MetS model using kidney-specific mosaic megalin knockout (KO) mice. Compared with control littermates fed a normal-fat diet, control litter mates fed an HFD for 12 weeks showed autolysosomal dysfunction with autophagy impairment and increased expression of hypertrophy, lipid peroxidation, and senescence markers in PTECs of the S2 segment, peritubular capillary rarefaction with localized interstitial fibrosis, and glomerular hypertrophy with mesangial expansion. These were ameliorated in HFD-fed megalin KO mice, even though these mice had the same levels of obesity, dyslipidemia, and hyperglycemia as HFD-fed control mice. Intravital renal imaging of HFD-fed wild-type mice also demonstrated the accumulation of autofluorescent lipofuscin-like substances in PTECs of the S2 segment, accompanied by focal narrowing of tubular lumens and peritubular capillaries. In cultured PTECs, fatty acid-rich albumin induced the increased expression of genes encoding PDGF-B and monocyte chemoattractant protein-1 via megalin, with large (auto)lysosome formation, compared with fatty acid-depleted albumin. Collectively, the megalin-mediated endocytic handling of glomerular-filtered (lipo)toxic substances appears to be involved primarily in hypertrophic and senescent PTEC injury with autophagy impairment, causing peritubular capillary damage and retrograde glomerular alterations in HFD-induced kidney disease. Megalin could be a therapeutic target for obesity/MetS-related CKD, independently of weight, dyslipidemia, and hyperglycemia modification.

    DOI： 10.1681/ASN.2015020190

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  • Reduction of Albuminuria by Sitagliptin Is Associated with Improvement of Renal Proximal Tubular Function in Patients with Type 2 Diabetes 査読

    Michihiro Hosojima, Taiji Sasagawa, Hideyuki Kabasawa, Tomomi Ishikawa, Ryohei Kaseda, Yoshiki Suzuki, Ichiei Narita, Hiroyuki Kurosawa, Yoshiaki Hirayama, Akihiko Saito

    DIABETES   64   A151 - A151   2015年6月

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    記述言語：英語   出版者・発行元：AMER DIABETES ASSOC  

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  • Dysfunctional high-density lipoproteins in children with chronic kidney disease 査読

    Ryohei Kaseda, Kathy Jabs, Tracy E. Hunley, Deborah Jones, Aihua Bian, Ryan M. Allen, Kasey C. Vickers, Patricia G. Yancey, MacRae F. Linton, Sergio Fazio, Valentina Kon

    METABOLISM-CLINICAL AND EXPERIMENTAL   64 ( 2 )   263 - 273   2015年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

    Objectives. Our aim was to determine if chronic kidney disease (CKD) occurring in childhood impairs the normally vasoprotective functions of high-density lipoproteins (HDLs).
    Materials and methods. HDLs were isolated from children with end-stage renal disease on dialysis (ESRD), children with moderate CKD and controls with normal kidney function. Macrophage response to HDLs was studied as expression of inflammatory markers (MCP-1, TNF-alpha, IL-1 beta) and chemotaxis. Human umbilical vein endothelial cells were used for expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and adhesion. Cellular proliferation, apoptosis, and necrosis of endothelial cells were measured by MTS/PMS reagent-based assay, flow cytometry, and ELISA. Cholesterol efflux was assessed by gas chromatographic measurements of cholesterol in macrophages exposed to HDLs.
    Results. Compared with HDLControl, HDLCKD and HDLESRD heightened the cytokine response and disrupted macrophage chemotaxis. HDLControl reduced endothelial expression of ICAM-1, VCAM-1, E-selectin, whereas HDLCKD and HDLESRD were less effective and showed reduced capacity to protect endothelial cells against monocyte adhesion. Compared with a dramatically enhanced endothelial proliferation following injurious stimulus by HDLControl, neither HDLCKD nor HDLESRD caused proliferative effects. HDLs of all three groups were equally protective against apoptosis assessed by flow cytometry and cleaved caspase-3 activity. Compared to HDLControl, HDLCKD and HDLESRD trended toward reduced capacity as cholesterol acceptors.
    Conclusion. CKD in children impairs HDL function. Even in the absence of long-standing and concomitant risk factors, CKD alters specific HDL functions linked to control of inflammation and endothelial responses. (C) 2015 Elsevier Inc. All rights reserved.

    DOI： 10.1016/j.metabol.2014.10.020

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  • Dysfunctional High-Density Lipoprotein in Patients on Chronic Hemodialysis 査読

    Suguru Yamamoto, Patricia G. Yancey, Alp Ikizler, W. Gray Jerome, Ryohei Kaseda, Brian Cox, Aihua Bian, Ayumi Shintani, Agnes B. Fogo, MacRae F. Linton, Sergio Fazio, Valentina Kon

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   60 ( 23 )   2372 - 2379   2012年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

    Objectives This study examined the functionality of high-density lipoprotein (HDL) in individuals with end-stage renal disease on dialysis (ESRD-HD).
    Background The high rate of cardiovascular disease (CVD) in chronic kidney disease is not explained by standard risk factors, especially in patients with ESRD-HD who appear resistant to benefits of statin therapy. HDL is antiatherogenic because it extracts tissue cholesterol and reduces inflammation.
    Methods Cellular cholesterol efflux and inflammatory response were assessed in macrophages exposed to HDL of patients with ESRD-HD or controls.
    Results HDL from patients with ESRD-HD was dramatically less effective than normal HDL in accepting cholesterol from macrophages (median 6.9%; interquartile range [IQR]: 1.4% to 10.2%) versus control (median 14.9%; IQR: 9.8% to 17.8%; p &lt; 0.001). The profound efflux impairment was also seen in patients with ESRD-HD and diabetes compared with patients with diabetes without renal disease (median 8.1%; IQR: 3.3% to 12.9%) versus control (median 13.6%; IQR: 11.0% to 15.9%; p = 0.009). In vitro activation of cellular cholesterol transporters increased cholesterol efflux to both normal and uremic HDL. HDL of patients with ESRD-HD had reduced anti-chemotactic ability and increased macrophage cytokine response (tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta). HDL of patients with ESRD-HD on statin therapy had reduced inflammatory response while maintaining impaired cholesterol acceptor function. Interestingly, impaired HDL-mediated efflux did not correlate with circulating C-reactive protein levels or cellular inflammatory response.
    Conclusions These findings suggest that abnormal HDL capacity to mediate cholesterol efflux is a key driver of excess CVD in patients on chronic hemodialysis and may explain why statins have limited effect to decrease CV events. The findings also suggest cellular cholesterol transporters as potential therapeutic targets to decrease CV risk in this population. (J Am Coll Cardiol 2012;60:2372-9) (C) 2012 by the American College of Cardiology Foundation

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  • Significance of Urinary Full-Length and Ectodomain Forms of Megalin in Patients With Type 2 Diabetes 査読

    Shinya Ogasawara, Michihiro Hosojima, Ryohei Kaseda, Hideyuki Kabasawa, Keiko Yamamoto-Kabasawa, Hiroyuki Kurosawa, Hiroyoshi Sato, Noriaki Iino, Tetsuro Takeda, Yoshiki Suzuki, Ichie Narita, Kunihiro Yamagata, Yasuhiko Tomino, Fumitake Gejyo, Yoshiaki Hirayama, Sakari Sekine, Akihiko Saito

    DIABETES CARE   35 ( 5 )   1112 - 1118   2012年5月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER DIABETES ASSOC  

    OBJECTIVE-Megalin, an endocytic receptor in proximal tubule cells, is involved in the mechanisms of albuminuria in diabetic nephropathy (DN). To develop efficient novel biomarkers associated with the pathogenesis of DN, we investigated urinary megalin excretion in type 2 diabetes.
    RESEARCH DESIGN AND METHODS-Sandwich enzyme-linked immunosorbent assay systems were established with monoclonal antibodies against the NH2 (amino [A]-megalin assay) and CO OH (C-megalin assay) termini of megalin to analyze urinary forms of megalin in 68 patients with type 2 diabetes.
    RESULTS-The A-megalin assay mainly detected a megalin ectodomain form in the soluble urinary fraction, whereas the C-megalin assay identified a full-length form in both soluble and insoluble fractions. Urinary C-megalin levels were significantly high in patients with normoalbuminuria, were elevated in line with increased albuminuria, and showed a better association with estimated glomerular filtration rate (eGFR) (&lt;60 mL/min/1.73 m(2)) than did urinary albumin. In contrast, urinary A-megalin levels were increased in patients with normo- and microalbuminuria but not in those with macroalbuminuria. Urinary C-megalin levels were also positively associated with plasma inorganic phosphate and negatively with hemoglobin levels in those showing no features of bleeding and not taking vitamin D analogs, phosphate binders, or erythropoiesis-stimulating agents.
    CONCLUSIONS-Urinary full-length megalin excretion as measured by the C-megalin assay is well associated with reduced eGFR and linked to the severity of DN, phosphate dysregulation, and anemia, whereas urinary excretion of megalin ectodomain as measured by the A-megalin assay may be associated with distinctive mechanisms of earlier DN in type 2 diabetes.

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  • Macrophage Polarization by Angiotensin II-Type 1 Receptor Aggravates Renal Injury-Acceleration of Atherosclerosis 査読

    Suguru Yamamoto, Patricia G. Yancey, Yiqin Zuo, Li-Jun Ma, Ryohei Kaseda, Agnes B. Fogo, Iekuni Ichikawa, MacRae F. Linton, Sergio Fazio, Valentina Kon

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   31 ( 12 )   2856 - U277   2011年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

    Objective-Angiotensin II is a major determinant of atherosclerosis. Although macrophages are the most abundant cells in atherosclerotic plaques and express angiotensin II type 1 receptor (AT1), the pathophysiologic role of macrophage AT1 in atherogenesis remains uncertain. We examined the contribution of macrophage AT1 to accelerated atherosclerosis in an angiotensin II-responsive setting induced by uninephrectomy (UNx).
    Methods and Results-AT1(-/-) or AT1(+/+) marrow from apolipoprotein E deficient (apoE(-/-)) mice was transplanted into recipient apoE-/- mice with subsequent UNx or sham operation: apoE(-/-)/AT1(+/+) -&gt; 3apoE(-/-) +sham; apoE(-/-)/AT1(+/+) 3apoE(-/-) +UNx; apoE(-/-)/AT1(-/-) -&gt; 3apoE(-/-) +sham; apoE(-/-)/AT1(-/-) -&gt; 3apoE(-/-) +UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the 2 UNx groups. ApoE(-/-)/AT1(+/+) 3apoE(-/-) +UNx had significantly more atherosclerosis (16907 +/- 21473 versus 116071 +/- 8180 mu m(2), P &lt; 0.05). By contrast, loss of macrophage AT1 which reduced local AT1 expression, prevented any effect of UNx on atherosclerosis (77174 +/- 9947 versus 75714 +/- 11333 mu m(2), P = NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE(-/-)/AT1(-/-) 3apoE(-/-) +UNx had fewer classically activated macrophage phenotype (M1) and more alternatively activated phenotype (M2). Further, UNx did not affect plaque necrosis or apoptosis in apoE(-/-)/AT1(-/-) 3apoE(-/-) whereas it significantly increased both (by 2- and 6-fold, respectively) in apoE(-/-)/AT1(+/+) 3apoE(-/-) mice. Instead, apoE(-/-)/AT1(-/-) 3apoE(-/-) had 5-fold-increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M2 macrophages, and a more efficient phagocytic function of AT1(-/-) macrophages versus AT1(+/+).
    Conclusion-AT1 receptor of bone marrow-derived macrophages worsens the extent and complexity of renal injury-induced atherosclerosis by shifting the macrophage phenotype to more M1 and less M2 through mechanisms that include increased apoptosis and impaired efferocytosis. (Arterioscler Thromb Vasc Biol. 2011;31:2856-2864.)

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  • Role of Megalin and Cubilin in the Metabolism of Vitamin D-3 査読

    Ryohei Kaseda, Michihiro Hosojima, Hiroyoshi Sato, Akihiko Saito

    THERAPEUTIC APHERESIS AND DIALYSIS   15   14 - 17   2011年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

    Vitamin D deficiency is associated with various medical conditions including musculoskeletal disorders, infection, metabolic diseases, and cardiovascular disease. Megalin and cubilin, endocytic receptors in proximal tubule cells, are involved in the reabsorption of vitamin D binding protein from glomerular filtrates and the subsequent intracellular conversion of 25-hydroxyvitamin D-3 to biologically active 1 alpha,25-dihydroxyvitamin D-3. Dysfunction of these receptors, which is commonly found in patients with diabetic nephropathy, even at early stages, may explain why vitamin D deficiency is often complicated in these patients. Therapeutic strategies to protect the functions of these receptors from injury could be used to prevent vitamin D deficiency and its related disorders.

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  • Megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells. 査読

    Takeyama A, Sato H, Soma-Nagae T, Kabasawa H, Suzuki A, Yamamoto-Kabasawa K, Hosojima M, Kaneko R, Higuchi F, Kaseda R, Ogasawara S, Narita I, Saito A

    Biochemical and biophysical research communications   407 ( 1 )   108 - 112   2011年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.1016/j.bbrc.2011.02.118

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  • Proximal tubule cell hypothesis for cardiorenal syndrome in diabetes. 査読

    Saito A, Kaseda R, Hosojima M, Sato H

    International journal of nephrology   2011   957164   2010年12月

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  • Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells 査読

    Kiyoko Hosaka, Tetsuro Takeda, Noriaki Iino, Michihiro Hosojima, Hiroyoshi Sato, Ryohei Kaseda, Keiko Yamamoto, Asako Kobayashi, Fumitake Gejyo, Akihiko Saito

    KIDNEY INTERNATIONAL   75 ( 12 )   1308 - 1315   2009年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

    Megalin plays a critical role in the endocytosis of albumin and other filtered low-molecular-weight proteins. Here we studied the interaction between megalin and Disabled-2 (Dab2), an adaptor protein that binds to the cytoplasmic domain of megalin and appears to control its trafficking. We co-immunoprecipitated megalin and Dab2 from cultured proximal tubule cells and identified the proteins by liquid chromatography and tandem mass spectrometry. We found two proteins associated with the megalin/Dab2 complex, nonmuscle myosin heavy chain IIA (NMHC-IIA) and beta-actin. Subcellular fractionation followed by sucrose velocity gradient separation showed that megalin, Dab2, and NMHC-IIA existed as a complex in the same endosomal fractions. In vitro pull-down assays demonstrated that NMHC-IIA was bound to the carboxyl-terminal region of Dab2, but not to megalin&apos;s cytoplasmic domain. We then transfected COS-7 cells with plasmids that induced the expression of Dab2, NMHC-IIA, and the megalin minireceptor, a truncated form of megalin. Co-immunoprecipitation studies showed that the minireceptor and NMHC-IIA co-immunoprecipitated only with Dab2. Furthermore, the uptake of (125)I-lactoferrin, an endocytic ligand of megalin, by rat yolk sac-derived megalin-expressing L2 cells was inhibited by blebbistatin, a specific inhibitor of nonmuscle myosin II. Our study shows that NMHC-IIA is functionally linked to megalin by interaction with Dab2 and is likely involved in megalin-mediated endocytosis in proximal tubule cells. Kidney International (2009) 75, 1308-1315; doi:10.1038/ki.2009.85; published online 1 April 2009

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  • Regulation of Megalin Expression in Cultured Proximal Tubule Cells by Angiotensin II Type 1A Receptor- and Insulin-Mediated Signaling Cross Talk 査読

    Michihiro Hosojima, Hiroyoshi Sato, Keiko Yamamoto, Ryohei Kaseda, Taeko Soma, Asako Kobayashi, Akiyo Suzuki, Hideyuki Kabasawa, Aya Takeyama, Kenji Ikuyama, Noriaki Iino, Akira Nishiyama, Thomas J. Thekkumkara, Tetsuro Takeda, Yoshiki Suzuki, Fumitake Gejyo, Akihiko Saito

    ENDOCRINOLOGY   150 ( 2 )   871 - 878   2009年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ENDOCRINE SOC  

    Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin&apos;s endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3- kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs. (Endocrinology 150: 871 - 878, 2009)

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  • Megalin-mediated endocytosis of cystatin C in proximal tubule cells 査読

    Ryohei Kaseda, Noriaki Iino, Michihiro Hosojima, Tetsuro Takeda, Kiyoko Hosaka, Asako Kobayashi, Keiko Yamamoto, Akiyo Suzuki, Ayaka Kasai, Yoshiki Suzuki, Fumitake Gejyo, Akihiko Saito

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   357 ( 4 )   1130 - 1134   2007年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Serum levels of cystatin C, an endogenous cysteine protemase inhibitor, are often used as an indicator of glomerular filtration rate. Although it is known that cystatin C is filtered by glomeruli and metabolized in proximal tubule cells (PTC), the precise molecular mechanism underlying this process is undetermined. Using quartz-crystal microbalance analyses, we demonstrate that cystatin C binds directly to megalin, an endocytic receptor in PTC, in a Ca(+)-dependent manner. We also find that cystatin C is endocytosed specifically via megalin in rat yolk sac epithelium-derived L2 cells which share a variety of characteristics with PTC. Finally, it? vivo studies using kidney-specific megalin knockout mice provide evidence that megalin mediates proximal tubular uptake of cystatin C. We conclude that megalin is an endocytic receptor of cystatin C in PTC. (c) 2007 Elsevier Inc. All rights reserved.

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  • Functional characterization of a novel missense CLCN5 mutation causing alterations in proximal tubular endocytic machinery in Dent's disease 査読

    Atsuhito Tanuma, Hiroyoshi Sato, Tetsuro Takeda, Michihiro Hosojima, Hiroaki Obayashi, Hitomi Hama, Noriaki Iino, Kiyoko Hosaka, Ryohei Kaseda, Naofumi Imai, Mitsuhiro Ueno, Maya Yamazaki, Kenji Sakimura, Fumitake Gejyo, Akihiko Saito

    NEPHRON PHYSIOLOGY   107 ( 4 )   P87 - P97   2007年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

    Background/Aims: Mutations of the endosomal chloride/ proton exchanger gene, CLCN5, cause Dent's disease, an X-linked recessive proximal tubular disorder. The renal endocytic system was found to be affected in clcn5 knockout mice. However, the impaired endocytic machinery of Dent's disease patients has not been thoroughly investigated. Methods: The CLCN5 gene was sequenced in a Japanese patient with Dent's disease and his family. The loss-of-function phenotype of the missense CLCN5 mutation was investigated by gene expression in Xenopus oocytes and CHO cells. Immunohistochemical analysis was performed on kidney biopsy specimens for endocytic machinery proteins, megalin, cubilin, and disabled-2 (Dab2) in proximal tubules. Results: Genomic analysis revealed a novel G-to-A transition at the first nucleotide of the 333rd codon of CLCN5, causing a substitution of glycine with arginine. Inefficient expression of the mutant gene in Xenopus oocytes resulted in abolished chloride currents. Impaired N-glycosylation of the mutant protein was evident in the DNA-transfected CHO cells. Proximal tubular expression of megalin, cubilin, and Dab2 was markedly reduced and irregular staining in some portions was observed in the patient compared with controls. Conclusions: A novel G333R CLCN5 mutation caused defective expression of megalin, cubilin, and Dab2 in a patient with Dent's disease. Copyright (c) 2007 S. Karger AG, Basel.

    DOI： 10.1159/000111253

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  • Functional characterization of a novel missense CLCN5 mutation causing alterations in proximal tubular endocytic machinery in Dent's disease. 査読

    Tanuma A, Sato H, Takeda T, Hosojima M, Obayashi H, Hama H, Iino N, Hosaka K, Kaseda R, Imai N, Ueno M, Yamazaki M, Sakimura K, Gejyo F, Saito A

    Nephron. Physiology   107 ( 4 )   p87 - 97   2007年

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  • Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis 査読

    A Saito, T Takeda, H Hama, Y Oyama, K Hosaka, A Tanuma, R Kaseda, M Ueno, S Nishi, S Ogasawara, F Gondaira, Y Suzuki, F Gejyo

    NEPHROLOGY   10   S26 - S31   2005年10月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

    Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin 11, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na(+) reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as &apos;protein metabolic overload hypothesis&apos;. Impaired metabolism of bioactive proteins such as angiotensin 11 and insulin in PTC may enhance hypertrophy of PTC and/or Na(+) reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.

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  • Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules 査読

    Y Oyama, T Takeda, H Hama, A Tanuma, N Iino, K Sato, R Kaseda, ML Ma, T Yamamoto, H Fujii, JJ Kazama, S Odani, Y Terada, K Mizuta, F Gejyo, A Saito

    LABORATORY INVESTIGATION   85 ( 4 )   522 - 531   2005年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

    Liver-type fatty acid binding protein (L-FABP) binds with high affinity to hydrophobic molecules including free fatty acid, bile acid and bilirubin, which are potentially nephrotoxic, and is involved in their metabolism mainly in hepatocytes. L-FABP is released into the circulation, and patients with liver damage have an elevated plasma L-FABP level. L-FABP is also present in renal tubules; however, the precise localization of L-FABP and its potential role in the renal tubules are not known. In this study, we examined the cellular and subcellular localization of L-FABP in the rat kidney and tried to determine from where the L-FABP in kidney tissues had originated. Immunohistochemical studies of kidney sections localized L-FABP in the lysosomes of proximal tubule cells (PTC). In rats with carbon tetrachloride (CCl(4))-induced acute liver injury, we detected high levels of L-FABP in the circulation and in the kidney compared with those in the control rat by immunoblotting, while reverse transcription-polymerase chain reaction showed that the level of L-FABP mRNA expression in the kidney of CCl(4)-treated rats was low and did not differ from that in the control rat. When (35)S-L-FABP was intravenously administered to rats, the kidneys took up (35)S-L-FABP more preferentially than the liver and heart, and histoautoradiography of kidney sections revealed that (35)S-L-FABP was internalized via the apical domains of PTC. Quartz-crystal microbalance analysis revealed that L-FABP bound to megalin, a multiligand endocytotic receptor on PTC, in a Ca(2+)-dependent manner. Degradation assays using megalin-expressing rat yolk sac tumor-derived L2 cells demonstrated that megalin mediated the cellular uptake and catabolism of (125)I-L-FABP. In conclusion, circulatory L-FABP was found to be filtered by glomeruli and internalized by PTC probably via megalin-mediated endocytosis. These results suggest a novel renal uptake pathway for L-FABP, a carrier of hydrophobic molecules, some of which may exert nephrotoxic effects.

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  • Significance of proximal ribular metabolism of advanced glycation end products in kidney diseases 査読

    A Saito, T Takeda, K Sato, H Hama, A Tanuma, R Kaseda, Y Suzuki, F Gejyo

    MAILLARD REACTION: CHEMISTRY AT THE INTERFACE OF NUTRITION, AGING, AND DISEASE   1043   637 - 643   2005年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NEW YORK ACAD SCIENCES  

    Advanced glycation end products (AGEs) are formed by the nonenzymatic Maillard reaction between sugars and proteins. Low-molecular weight AGES are filtered by renal glomeruli and then reabsorbed and metabolized by proximal tubule cells (PTCs). High-molecular weight AGES are also delivered to PTCs in proteinuric states. In patients with diabetes, AGE generation is increased, and the actions of AGES on PTCs are likely involved in the pathogenesis of diabetic nephropathy. In patients with chronic renal failure (CRF), reduced renal metabolism of AGEs likely accounts for the accumulation of AGEs in serum, leading to uremic complications including dialysis-related amyloidosis. AGE precursors such as reactive carbonyl compounds also accumulate in the sera of patients with CRF. It is likely that PTCs take up AGEs and AGE precursors via specific endocytotic receptors or transporters. Megalin is a multiligand endocytotic receptor that is abundantly expressed on PTCs. There is evidence that megalin is involved in the cellular uptake and degradation of AGES. We previously reported a cell therapy model involving implantation of megalin-expressing cells into experimental mice with renal failure for elimination of uremic toxin proteins. Further studies are needed to clarify the molecular mechanisms of the metabolism of AGEs and their precursors to develop a strategy

    DOI： 10.1196/annals.1333.072

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書籍等出版物

  • 腎臓内科・泌尿器科

    忰田 亮平（ 担当： 分担執筆 ,  範囲: 腎泌尿器の難病研究）

    科学評論社  2019年 

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  • 臨床検査増刊号「重要疾患レッドページ」

    忰田 亮平（ 担当： 分担執筆 ,  範囲: ネフローゼ症候群）

    医学書院  2019年 

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  • 腎と透析 ベッドサイド検査事典

    忰田 亮平（ 担当： 分担執筆 ,  範囲: 腎静態シンチグラフィ一（99mTc-DMSA法）, 腎動態シンチグラフィ一（99mTc-DTPA法，99mTc-MAG3法））

    東京医学社  2018年 

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  • 「内分泌・糖尿病・代謝内科」特集/ガイドラインに基づく糖質調整とその実際

    忰田 亮平（ 担当： 分担執筆 ,  範囲: 腎症・脂質代謝異常と糖質調整）

    科学評論社  2016年 

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  • Annual Review 腎臓 2015

    忰田 亮平（ 担当： 分担執筆 ,  範囲: B.尿細管・間質障害 (1) タンパク質代謝臓器としての腎）

    中外医学社  2015年 

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  • Medical Practice 2015年(vol.32) 臨時増刊号 病態生理と症例から学ぶ輸液ガイド

    忰田 亮平（ 担当： 分担執筆 ,  範囲: 15 慢性腎炎、ネフローゼ症候群患者の輸液法）

    文光堂  2015年 

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  • 腎と透析

    忰田 亮平（ 担当： 分担執筆 ,  範囲: 尿潜血・血尿・色素尿からわかる腎臓病）

    東京医学社  2015年 

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MISC

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講演・口頭発表等

  • Establishment of a virtual slide system linking to the Japan Renal Biopsy Registry 国際会議

    忰田 亮平

    American Society of Nephrology Annual Meeting Kidney Week 2019. Washington DC  2019年11月 

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    記述言語：英語   会議種別：ポスター発表  

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  • バーチャルスライドの登録状況報告

    忰田 亮平

    第62回日本腎臓学会学術総会 名古屋市  2019年6月 

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    記述言語：日本語   会議種別：口頭発表（一般）  

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  • Plant versus animal protein improves anti-inflammatory effects of HDL and lessens CKD-induced atherosclerosis

    忰田 亮平

    第61回日本腎臓学会総会 新潟県 新潟市  2018年6月 

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    記述言語：英語   会議種別：口頭発表（一般）  

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  • Plant protein compared to animal protein improves anti-inflammatory effects of HDL and lessens CKD-induced atherosclerosis 国際会議

    忰田 亮平

    ISN FRONTIERS MEETINGS Tokyo, Japan  2018年2月 

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    記述言語：英語   会議種別：ポスター発表  

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  • Plant versus animal protein improves anti-inflammatory effects of HDL and lessens CKD-induced atherosclerosis 国際会議

    忰田 亮平

    American Society of Nephrology Annual Meeting Kidney Week 2017. New Orleans, LA  2017年10月 

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    記述言語：英語   会議種別：ポスター発表  

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  • Differential effects of angiotensin II receptor blocker (ARB) vs ACE inhibitor (ACEI) on HDL functionality in patients on maintenance hemodialysis (MHD) 国際会議

    忰田 亮平

    American Society of Nephrology Annual Meeting Kidney Week 2016.Chicago,IL  2016年11月 

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    記述言語：英語   会議種別：ポスター発表  

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  • レニン‐アンジオテンシン系(RAS)阻害薬の血液透析患者(HD)HDLへの効果

    忰田 亮平

    第61回日本透析医学会学術集会・総会 大阪府 大阪市  2016年6月 

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    記述言語：日本語   会議種別：ポスター発表  

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  • Efficacy of nutrition counseling intake restriction in chronic kidney disease patients-Niigata part of SOFT-J(study on Rejional variation of FROM-J intervention by Japanese Society of Nephrology) 国際会議

    忰田 亮平

    American Society of Nephrology Annual Meeting Kidney Week 2015. San Diego,CA  2015年11月 

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    記述言語：英語   会議種別：ポスター発表  

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  • CKD患者に対するたんぱく質摂取制限指導の検証：SOFT-J study

    忰田 亮平

    第58回日本腎臓学会学術集会 愛知県 名古屋市  2015年6月 

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    記述言語：日本語   会議種別：ポスター発表  

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  • Disruption of Macrophage Lipid and Inflammatory Handling and Effects of Liver X Recepter(LXR)Agonism

    忰田 亮平

    American Society of Nephrology Kidney Week 2014 Philadelphia, PA  2014年11月 

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    記述言語：英語  

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  • Childhood Chronic Kidney Disease (CKD) Impairs Normal Vasoprotective Functions of High Density Lipoprotein (HDL) 国際会議

    忰田 亮平

    American Society of Nephrology Kidney Week 2013 Atlanta, GA  2013年11月 

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    記述言語：英語   会議種別：口頭発表（一般）  

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  • Chronic Kidney Disease (CKD) in Children Impairs Normal Protective Functions of High Density Lipoprotein (HDL) 国際会議

    忰田 亮平

    Pediatric Academic Societies Annual Meeting 2013. Washington DC  2013年5月 

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    記述言語：英語   会議種別：ポスター発表  

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  • Chronic Kidney Disease (CKD) in Children Impairs Normal Protective Functions of High Density Lipoprotein (HDL) 国際会議

    忰田 亮平

    American Society of Nephrology 45th Annual Meeting. San Diego, CA  2012年11月 

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    記述言語：英語   会議種別：ポスター発表  

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受賞

  • TOP10% poster

    2018年2月   ISN FRONTIERS MEETING   Plant versus animal protein improves anti-inflammatory effects of HDL and lessens CKD-induced atherosclerosis

    忰田 亮平

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  • Top Oral Abstracts by Trainees

    2013年11月   第46回米国腎臓学会総会   Childhood Chronic Kidney Disease (CKD) Impairs Normal Vasoprotective Functions of High Density Lipoprotein (HDL)

    忰田 亮平

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  • The ASPN Presentation Award

    2013年5月   米国小児科学会議 2013   Chronic Kidney Disease (CKD) in Children Impairs Normal Protective Functions of High Density Lipoprotein (HDL)

    忰田 亮平

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  • AEA受賞

    2010年12月   Advans研究会   近位尿細管上皮細胞エンドサイトーシス受容体メガリンの発現調節機構

    忰田 亮平

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  • CKD award2010 ポスター発表奨励賞

    2010年11月   メタボリックシンドローム関連腎症の発症・進展機序におけるメガリンの関与

    忰田 亮平

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共同研究・競争的資金等の研究

  • 多彩な解析情報を得る機能的NMRの生組織への展開と生態の所望部位を可視化するMRIの開発 研究参加者

    2018年8月 - 2021年3月

    文部科学省  AMED 医療分野成果研究事業（先端計測分析技術・機器開発プログラム） 

    佐々木 進

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    資金種別：競争的資金

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  • ネフローゼ症候群の新規診断法の確立 研究参加者

    2018年4月 - 2021年3月

    文部科学省  AMED 難治性疾患実用化研究事業（診療に直結するエビデンス創出研究） 

    丸山 彰一

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    資金種別：競争的資金

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  • メガリンの機能抑制によるスフィンゴシン1-リン酸を介した動脈硬化軽減作用の検証

    2018年4月 - 2019年3月

    新潟県医師会  学術研究助成金 

    忰田 亮平

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    担当区分：研究代表者  資金種別：競争的資金

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  • 難治性腎障害に関する調査研究 研究分担者

    2017年4月 - 2020年3月

    厚生労働省  科学研究費補助金 

    成田 一衛

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    資金種別：競争的資金

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  • SGLT2阻害薬の腎保護機序と診断法

    2017年4月 - 2018年3月

    臨床薬理研究振興財団  研究奨励金 

    忰田 亮平

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    担当区分：研究代表者  資金種別：競争的資金

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  • メガリンを標的とした腎機能温存・再生療法の開発 研究分担者

    2016年4月 - 2019年3月

    文部科学省  AMED 腎疾患実用化事業 

    斎藤 亮彦

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    資金種別：競争的資金

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  • メガリンを介した心腎関連機序とﾀﾝﾊﾟｸ質代謝の関連

    2015年10月 - 2017年9月

    (公財)万有生命科学振興国際交流財団  研究助成 

    忰田 亮平

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    担当区分：研究代表者  資金種別：競争的資金

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  • 新しい心腎連関機序：メガリンの発現抑制による腎保護を介した動脈硬化軽減作用の検証

    2015年4月 - 2018年3月

    文部科学省  科学研究費助成事業(学術研究助成基金助成金) 若手研究(B) 

    忰田 亮平

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    担当区分：研究代表者  資金種別：競争的資金

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▶ 全件表示

 

社会貢献活動

  • 脂質異常症と動脈硬化症について

    役割：講師

    新潟市  第25期（2019年）にいがた市民大学  2019年7月

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  • イオンシネマ健康フェスティバル 健康な生活を送るために

    役割：講師

    2017年9月

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メディア報道

  • みんなの診察室. 新潟日報 新聞・雑誌

    2018年5月

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  • メガリンの機能抑制によるスフィンゴシン１-リン酸を介した動脈硬化軽減作用の検証

    新潟県医師会報  2018年

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