Faculty Profiles - SAITO Akihiko

Papers - SAITO Akihiko

Division display 1 - 20 of about 162 ／ All the affair displays >>

Fanconi syndrome with acute proximal tubular injury induced by a dietary supplement containing beni-koji: a case series report. International journal

Masato Habuka, Michihiro Hosojima, Yusuke Yata, Kenshiro Kurumada, Moeri Yamagiwa, Masataka Yonezawa, Masanori Sudo, Hideyuki Kabasawa, Asa Ogawa, Hitomi Hama, Yumi Ito, Naofumi Imai, Suguru Yamamoto, Akihiko Saito, Shin Goto

BMC nephrology 25 ( 1 ) 446 - 446 2024.12

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

BACKGROUND: Fanconi syndrome is a disorder of the proximal tubule that leads to malabsorption of various electrolytes and substances and is a common consequence of drug-induced nephrotoxicity. However, cases of dietary supplement-induced Fanconi syndrome are rare, and detailed reports on the evaluation of renal histology in patients with this syndrome are lacking. CASE PRESENTATION: We present two cases of dietary supplement-induced Fanconi syndrome that was confirmed by kidney biopsy. Based on their medical history and laboratory and histological findings, both cases were diagnosed as acute proximal tubular injury caused by ingestion of a lipid-lowering dietary supplement containing beni-koji leading to Fanconi syndrome. After discontinuation of the dietary supplement and correction of dehydration and electrolyte imbalance, renal function completely recovered in one case but progressed to chronic kidney disease in the other. CONCLUSIONS: Clinicians should consider dietary supplement-induced Fanconi syndrome as a differential diagnosis in patients who become ill while taking a dietary supplement. Kidney biopsy is useful for diagnosing acute tubular injury with Fanconi syndrome and investigating its pathogenesis. Patients who have developed dietary supplement-induced Fanconi syndrome require long-term monitoring to detect and prevent progression to chronic kidney disease.

DOI： 10.1186/s12882-024-03903-5

PubMed

researchmap

Development of sandwich enzyme-linked immunosorbent assays quantifying mouse urinary megalin, a novel proximal tubular biomarker. International journal

Rina Sofuku, Sayaka Miyazaki, Michihiro Hosojima, Sawako Goto, Kazuya Takemoto, Hideyuki Kabasawa, Taeko Endo, Koichi Komochi, Nanako Sugita, Hiroyuki Aoki, Ryota Kobayashi, Ichiei Narita, Akihiko Saito

Journal of immunological methods 534 113763 - 113763 2024.11

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

Megalin, a type I transmembrane protein, serves as a multi-ligand endocytic receptor in the apical membrane of proximal tubules. Its ectodomain and full-length forms are excreted into human urine, with the former being more abundant. We previously developed two types of sandwich enzyme-linked immunosorbent assays (ELISAs) utilizing monoclonal antibodies that target the amino-terminal ligand-binding domain-I and the carboxyl-terminal cytoplasmic region of human megalin, respectively. The former, termed "A-megalin" ELISA, primarily identifies ectodomains of megalin, whereas the latter, "C-megalin" ELISA, specifically recognizes full-length megalin originating from urinary extracellular vesicles. This study developed novel sandwich ELISAs to assess mouse urinary A-megalin and C-megalin, thereby facilitating studies involving these biomarkers in mouse disease models. Immunoblotting and immunohistochemistry of monoclonal antibodies against human megalin were performed to assess their compatibility with mouse megalin in novel sandwich ELISAs, which were constructed and validated using human assay protocols. Immunoblot analysis of megalin in urinary extracellular vesicles and supernatant was performed to investigate the ratio of ectodomain to full-length forms in mouse urine. Stable measurements having a precision and accuracy within 15 % were achieved in the measurement of quality control samples. A-megalin and C-megalin were detectable in the urine of C57BL/6 mice, whereas most urine samples from kidney-specific conditional megalin-knockout mice were below detection limits. Ectodomain forms of megalin were at least approximately 70 times more abundant than the full-length form, even in mouse urine. In conclusion, we successfully developed sandwich ELISAs for assessing mouse urinary A-megalin and C-megalin to evaluate primarily ectodomain and full-length forms of megalin, respectively.

DOI： 10.1016/j.jim.2024.113763

PubMed

researchmap

Changes in daily intake of nutrients and foods including confectionery after the initiation of empagliflozin in Japanese patients with type 2 diabetes: a pilot study. International journal

Toshiko Murayama, Michihiro Hosojima, Hideyuki Kabasawa, Takahiro Tanaka, Nobutaka Kitamura, Mai Tanaka, Shoji Kuwahara, Yoshiki Suzuki, Ichiei Narita, Akihiko Saito

BMC nutrition 10 ( 1 ) 95 - 95 2024.7

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

INTRODUCTION: It is unclear how dietary intake changes after sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is started in patients with type 2 diabetes. METHODS: We performed a non-controlled, open-label study that enrolled 51 patients with type 2 diabetes. The patients were newly administered empagliflozin, and their dietary habits were examined using a self-administered diet history questionnaire at the beginning of the study and after 24 weeks. We investigated the association of changes in HbA1c and body weight with changes in energy, nutrient, and food group intakes. RESULTS: At 24 weeks after the start of the study, HbA1c improved significantly and body weight decreased. In the food group, only the intake of confectionery increased, and there were no significant differences in the association between changes in HbA1c and body weight and changes in energy, nutrient, and food group intakes after 24 weeks. However, a significant negative correlation was found between change in HbA1c after 4 weeks and change in energy intake after 24 weeks, and principal component analysis showed an association between change in HbA1c levels after 4 weeks and change in energy intake and some food group intakes including confectionery after 24 weeks. CONCLUSION: In this study, after 24 weeks of treatment with empagliflozin, only intake of confectionery increased. Early assessment by dietitians after initiation of SGLT2i treatment might be important because our data suggested that the reduction in blood glucose levels after the start of empagliflozin was associated with a subsequent increase in energy intake. TRIAL REGISTRATION: University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on September 5, 2016 (registration ID, UMIN000002309|| http://www.umin.ac.jp/ctr/ ).

DOI： 10.1186/s40795-024-00902-5

PubMed

researchmap

メガリン機能抑制を介したSGLT2阻害薬による腎保護機序

竹本和矢, 細島康宏, 後藤佐和子, 蒲澤秀門, 杉田奈々子, 遠藤多恵子, 青木弘行, 小餅耕一, 成田一衛, 斎藤亮彦

日本腎臓学会誌 66 ( 4 ) 581 - 581 2024.6

Cryo-EM structures elucidate the multiligand receptor nature of megalin. International journal

Sawako Goto, Akihisa Tsutsumi, Yongchan Lee, Michihiro Hosojima, Hideyuki Kabasawa, Koichi Komochi, Satoru Nagatoishi, Kazuya Takemoto, Kouhei Tsumoto, Tomohiro Nishizawa, Masahide Kikkawa, Akihiko Saito

Proceedings of the National Academy of Sciences of the United States of America 121 ( 22 ) e2318859121 2024.5

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

Megalin (low-density lipoprotein receptor-related protein 2) is a giant glycoprotein of about 600 kDa, mediating the endocytosis of more than 60 ligands, including those of proteins, peptides, and drug compounds [S. Goto, M. Hosojima, H. Kabasawa, A. Saito, Int. J. Biochem. Cell Biol. 157, 106393 (2023)]. It is expressed predominantly in renal proximal tubule epithelial cells, as well as in the brain, lungs, eyes, inner ear, thyroid gland, and placenta. Megalin is also known to mediate the endocytosis of toxic compounds, particularly those that cause renal and hearing disorders [Y. Hori et al., J. Am. Soc. Nephrol. 28, 1783-1791 (2017)]. Genetic megalin deficiency causes Donnai-Barrow syndrome/facio-oculo-acoustico-renal syndrome in humans. However, it is not known how megalin interacts with such a wide variety of ligands and plays pathological roles in various organs. In this study, we elucidated the dimeric architecture of megalin, purified from rat kidneys, using cryoelectron microscopy. The maps revealed the densities of endogenous ligands bound to various regions throughout the dimer, elucidating the multiligand receptor nature of megalin. We also determined the structure of megalin in complex with receptor-associated protein, a molecular chaperone for megalin. The results will facilitate further studies on the pathophysiology of megalin-dependent multiligand endocytic pathways in multiple organs and will also be useful for the development of megalin-targeted drugs for renal and hearing disorders, Alzheimer's disease [B. V. Zlokovic et al., Proc. Natl. Acad. Sci. U.S.A. 93, 4229-4234 (1996)], and other illnesses.

DOI： 10.1073/pnas.2318859121

PubMed

researchmap

Megalin-related mechanism of hemolysis-induced acute kidney injury and the therapeutic strategy. International journal

Sawako Goto, Michihiro Hosojima, Hideyuki Kabasawa, Kaho Arai, Kazuya Takemoto, Hiroyuki Aoki, Koichi Komochi, Ryota Kobayashi, Nanako Sugita, Taeko Endo, Ryohei Kaseda, Yutaka Yoshida, Ichiei Narita, Yoshiaki Hirayama, Akihiko Saito

The Journal of pathology 2024.5

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

Hemolysis-induced acute kidney injury (AKI) is attributed to heme-mediated proximal tubule epithelial cell (PTEC) injury and tubular cast formation due to intratubular protein condensation. Megalin is a multiligand endocytic receptor for proteins, peptides, and drugs in PTECs and mediates the uptake of free hemoglobin and the heme-scavenging protein α1-microglobulin. However, understanding of how megalin is involved in the development of hemolysis-induced AKI remains elusive. Here, we investigated the megalin-related pathogenesis of hemolysis-induced AKI and a therapeutic strategy using cilastatin, a megalin blocker. A phenylhydrazine-induced hemolysis model developed in kidney-specific mosaic megalin knockout (MegKO) mice confirmed megalin-dependent PTEC injury revealed by the co-expression of kidney injury molecule-1 (KIM-1). In the hemolysis model in kidney-specific conditional MegKO mice, the uptake of hemoglobin and α1-microglobulin as well as KIM-1 expression in PTECs was suppressed, but tubular cast formation was augmented, likely due to the nonselective inhibition of protein reabsorption in PTECs. Quartz crystal microbalance analysis revealed that cilastatin suppressed the binding of megalin with hemoglobin and α1-microglobulin. Cilastatin also inhibited the specific uptake of fluorescent hemoglobin by megalin-expressing rat yolk sac tumor-derived L2 cells. In a mouse model of hemolysis-induced AKI, repeated cilastatin administration suppressed PTEC injury by inhibiting the uptake of hemoglobin and α1-microglobulin and also prevented cast formation. Hemopexin, another heme-scavenging protein, was also found to be a novel ligand of megalin, and its binding to megalin and uptake by PTECs in the hemolysis model were suppressed by cilastatin. Mass spectrometry-based semiquantitative analysis of urinary proteins in cilastatin-treated C57BL/6J mice indicated that cilastatin suppressed the reabsorption of a limited number of megalin ligands in PTECs, including α1-microglobulin and hemopexin. Collectively, cilastatin-mediated selective megalin blockade is an effective therapeutic strategy to prevent both heme-mediated PTEC injury and cast formation in hemolysis-induced AKI. © 2024 The Pathological Society of Great Britain and Ireland.

DOI： 10.1002/path.6284

PubMed

researchmap

The structure of the rat vitamin B12 transporter TC and its complex with glutathionylcobalamin. International journal

Marcel Bokhove, Takashi Kawamura, Hideo Okumura, Sawako Goto, Yoshiaki Kawano, Stefan Werner, Franziska Jarczowski, Victor Klimyuk, Akihiko Saito, Takashi Kumasaka

The Journal of biological chemistry 300 ( 5 ) 107289 - 107289 2024.5

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

Vitamin B12 (cobalamin or Cbl) functions as a cofactor in two important enzymatic processes in human cells, and life is not sustainable without it. B12 is obtained from food and travels from the stomach, through the intestine, and into the bloodstream by three B12-transporting proteins: salivary haptocorrin (HC), gastric intrinsic factor, and transcobalamin (TC), which all bind B12 with high affinity and require proteolytic degradation to liberate Cbl. After intracellular delivery of dietary B12, Cbl in the aquo/hydroxocobalamin form can coordinate various nucleophiles, for example, GSH, giving rise to glutathionylcobalamin (GSCbl), a naturally occurring form of vitamin B12. Currently, there is no data showing whether GSCbl is recognized and transported in the human body. Our crystallographic data shows for the first time the complex between a vitamin B12 transporter and GSCbl, which compared to aquo/hydroxocobalamin, binds TC equally well. Furthermore, sequence analysis and structural comparisons show that TC recognizes and transports GSCbl and that the residues involved are conserved among TCs from different organisms. Interestingly, haptocorrin and intrinsic factor are not structurally tailored to bind GSCbl. This study provides new insights into the interactions between TC and Cbl.

DOI： 10.1016/j.jbc.2024.107289

PubMed

researchmap

Megalin is involved in angiotensinogen-induced, angiotensin II-mediated ERK1/2 signaling to activate Na+-H+ exchanger 3 in proximal tubules. Reviewed International journal

Sawako Goto, Yutaka Yoshida, Michihiro Hosojima, Shoji Kuwahara, Hideyuki Kabasawa, Hiroyuki Aoki, Tomomichi Iida, Ryuhei Sawada, Daisuke Ugamura, Yuta Yoshizawa, Kazuya Takemoto, Koichi Komochi, Ryota Kobayashi, Ryohei Kaseda, Eishin Yaoita, Satoru Nagatoishi, Ichiei Narita, Kouhei Tsumoto, Akihiko Saito

Journal of hypertension 2023.9

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

BACKGROUND: Kidney angiotensin (Ang) II is produced mainly from liver-derived, glomerular-filtered angiotensinogen (AGT). Podocyte injury has been reported to increase the kidney Ang II content and induce Na+ retention depending on the function of megalin, a proximal tubular endocytosis receptor. However, how megalin regulates the renal content and action of Ang II remains elusive. METHODS: We used a mass spectrometry-based, parallel reaction-monitoring assay to quantitate Ang II in plasma, urine, and kidney homogenate of kidney-specific conditional megalin knockout (MegKO) and control (Ctl) mice. We also evaluated the pathophysiological changes in both mouse genotypes under the basal condition and under the condition of increased glomerular filtration of AGT induced by administration of recombinant mouse AGT (rec-mAGT). RESULTS: Under the basal condition, plasma and kidney Ang II levels were comparable in the two mouse groups. Ang II was detected abundantly in fresh spot urine in conditional MegKO mice. Megalin was also found to mediate the uptake of intravenously administered fluorescent Ang II by PTECs. Administration of rec-mAGT increased kidney Ang II, exerted renal extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, activated proximal tubular Na+-H+ exchanger 3 (NHE3), and decreased urinary Na+ excretion in Ctl mice, whereas these changes were suppressed but urinary Ang II was increased in conditional MegKO mice. CONCLUSION: Increased glomerular filtration of AGT is likely to augment Ang II production in the proximal tubular lumen. Thus, megalin-dependent Ang II uptake should be involved in the ERK1/2 signaling that activates proximal tubular NHE3 in vivo, thereby causing Na+ retention.

DOI： 10.1097/HJH.0000000000003555

PubMed

researchmap

ステロイド糖尿病の経過中に両側非定型大腿骨不全骨折を生じた1例

渡邉和樹, 黒澤陽一, 長谷川絵理子, 若松彩子, 蒲澤秀門, 細島康宏, 佐藤弘恵, 中枝武司, 鈴木芳樹, 斎藤亮彦, 成田一衛

糖尿病 66 ( 7 ) 567 - 567 2023.7

【尿細管機能異常の臨床】腎障害における尿細管慢性腎臓病と尿細管機能

細島康宏, 蒲澤秀門, 後藤佐和子, 斎藤亮彦

腎臓内科 17 ( 5 ) 505 - 512 2023.5

3ヵ月間の生活習慣改善が血清レプチンとアルブミン尿に与える影響肥満の効果修飾について

蒲澤佳子, 細島康宏, 伊藤由美, 成田一衛, 斎藤亮彦

日本腎臓学会誌 65 ( 3 ) 318 - 318 2023.5

SGLT2阻害薬使用時におけるメガリンおよびメガリンリガンドの尿中排泄量の推移

細島康宏, 蒲澤秀門, 田中崇裕, 北村信隆, 後藤佐和子, 鈴木芳樹, 成田一衛, 斎藤亮彦

日本腎臓学会誌 65 ( 3 ) 319 - 319 2023.5

メガリンが関与する造影剤腎症の発症メカニズムの解明とその予防法の開発

後藤佐和子, 細島康宏, 蒲澤秀門, 忰田亮平, 成田一衛, 斎藤亮彦

日本腎臓学会誌 65 ( 3 ) 248 - 248 2023.5

シスプラチンを含むがん化学療法におけるシラスタチンの急性腎障害予防効果を検討するための薬物動態試験

蒲澤秀門, 細島康宏, 後藤佐和子, 田中崇裕, 北村信隆, 成田一衛, 斎藤亮彦

日本腎臓学会誌 65 ( 3 ) 274 - 274 2023.5

The endocytosis receptor megalin: From bench to bedside. International journal

Sawako Goto, Michihiro Hosojima, Hideyuki Kabasawa, Akihiko Saito

The international journal of biochemistry & cell biology 157 106393 - 106393 2023.4

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

The large (∼600 kDa) endocytosis receptor megalin/low-density lipoprotein receptor-related protein 2 is highly expressed at the apical membrane of proximal tubular epithelial cells (PTECs). Megalin plays an important role in the endocytosis of various ligands via interactions with intracellular adaptor proteins, which mediate the trafficking of megalin in PTECs. Megalin mediates the retrieval of essential substances, including carrier-bound vitamins and elements, and impairment of the endocytic process may result in the loss of those substances. In addition, megalin reabsorbs nephrotoxic substances such as antimicrobial (colistin, vancomycin, and gentamicin) or anticancer (cisplatin) drugs and advanced glycation end product-modified or fatty acid-containing albumin. The megalin-mediated uptake of these nephrotoxic ligands causes metabolic overload in PTECs and leads to kidney injury. Blockade or suppression of the megalin-mediated endocytosis of nephrotoxic substances may represent a novel therapeutic strategy for drug-induced nephrotoxicity or metabolic kidney disease. Megalin reabsorbs urinary biomarker proteins such as albumin, α1-microglobulin, β2-microglobulin, and liver-type fatty acid-binding protein; thus, the above-mentioned megalin-targeted therapy may have an effect on the urinary excretion of these biomarkers. We have previously established a sandwich enzyme-linked immunosorbent assay to measure the ectodomain (A-megalin) and full-length (C-megalin) forms of urinary megalin using monoclonal antibodies against the amino- and carboxyl-terminals of megalin, respectively, and reported their clinical usefulness. In addition, there have been reports of patients with novel pathological anti-brush border autoantibodies targeting megalin in the kidney. Even with these breakthroughs in the characterization of megalin, a large number of issues remain to be addressed in future research.

DOI： 10.1016/j.biocel.2023.106393

PubMed

researchmap

臨床現場における糖尿病性腎症のマネージメント CKDの食事療法における低たんぱく質ご飯の有用性

細島康宏, 蒲澤秀門, 鈴木芳樹, 斎藤亮彦, 成田一衛

糖尿病 66 ( Suppl.1 ) S - 43 2023.4

SGLT2阻害薬使用時における尿中メガリンおよびメガリンリガンド分子の動態

細島康宏, 蒲澤秀門, 田中崇裕, 北村信隆, 後藤佐和子, 鈴木芳樹, 成田一衛, 斎藤亮彦

糖尿病 66 ( Suppl.1 ) S - 286 2023.4

血液透析中の食事摂取状況と新型コロナウイルス感染症(COVID-19)流行の影響に関する連続横断研究

蒲澤秀門, 細島康宏, 斎藤亮彦, 鈴木芳樹, 成田一衛

日本病態栄養学会誌 26 ( Suppl. ) S - 55 2023.1

A case of idiopathic nodular glomerulosclerosis successfully treated by intensive blockade of the renin-angiotensin-aldosterone system.

Hiroki Yamaguchi, Michihiro Hosojima, Hideyuki Kabasawa, Yumi Ito, Yoshiki Suzuki, Akihiko Saito, Masaaki Arakawa, Ichiei Narita

CEN case reports 2022.12

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

Idiopathic nodular glomerulosclerosis has a poor renal prognosis and is characterized by diffuse nodular glomerulosclerotic lesions in the absence of diabetic mellitus. Here, we report the case of a 69-year-old woman with no smoking history who developed renal dysfunction and proteinuria in the absence of overt diabetes or obesity. A biopsy specimen showed nodular mesangial sclerosis with arteriolar hyalinosis and severe large-vessel arteriosclerosis, leading to a diagnosis of idiopathic nodular glomerulosclerosis. Addition of esaxerenone to her existing renin-angiotensin-aldosterone inhibitor therapy led to a rapid decrease in the proteinuria levels and the maintenance of renal function without any complications for more than a year. The results suggest that intensive renin-angiotensin-aldosterone blockade might be an effective treatment for idiopathic nodular glomerulosclerosis.

DOI： 10.1007/s13730-022-00766-3

PubMed

researchmap

Efficacy of Low-Protein Rice for Dietary Protein Restriction in CKD Patients: A Multicenter, Randomized, Controlled Study. International journal

Michihiro Hosojima, Hideyuki Kabasawa, Ryohei Kaseda, Tomomi Ishikawa-Tanaka, Yoshitsugu Obi, Toshiko Murayama, Shoji Kuwahara, Yoshiki Suzuki, Ichiei Narita, Akihiko Saito

Kidney360 3 ( 11 ) 1861 - 1870 2022.11

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

BACKGROUND: The benefits of dietary protein restriction in CKD remain unclear, largely due to inadequate adherence in most clinical trials. We examined whether low-protein rice (LPR) previously developed to reduce the protein content of rice, a major staple food, would help improve adherence to dietary protein restriction. METHODS: This open-label, multicenter, randomized, controlled trial evaluated the efficacy of LPR use for reducing dietary protein intake (DPI) in patients with CKD stages G3aA2-G4. Participants were randomly assigned in a 1:1 ratio to an LPR or control group and were followed up for 24 weeks. Both groups received regular counseling by dietitians to help achieve a target DPI of 0.7 g/kg ideal body weight (IBW) per day. The amount of protein in LPR is about 4% of that in ordinary rice, and the participants in the LPR group were instructed to consume LPR with at least two meals per day. The primary outcome was estimated dietary protein intake (eDPI) determined using the Maroni formula. The secondary outcomes included creatinine clearance (CCr) and urinary protein on the basis of 24-hour urine collection. RESULTS: In total, 51 patients were randomized to either the LPR group or the control group. At baseline, mean age was 62.5 years, 70% were men, mean CCr was 52.0 ml/min, and mean eDPI was 0.99 g/kg IBW per day. At 24 weeks, mean eDPI decreased to 0.80 g/kg IBW per day in the LPR group and to 0.91 g/kg IBW per day in the control group, giving a between-group difference of 0.11 g/kg IBW per day (95% confidence interval, 0.03 to 0.19 g/kg IBW per day; P=0.006). There was no significant between-group difference in CCr, but urinary protein was lower at 24 weeks in the LPR group than in the control group. CONCLUSIONS: LPR is a feasible tool for efficiently reducing DPI in patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Randomized, Multicenter, Controlled Study for the Efficacy of Low-Protein Rice Diet in Patients with Chronic Kidney Disease, UMIN000015630.

DOI： 10.34067/KID.0002982022

PubMed

researchmap

　 PREV - NEXT 　

<SAITO Akihiko>

Papers - SAITO Akihiko