研究者業績
基本情報
研究キーワード
5経歴
5-
2017年5月
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2013年4月 - 2017年4月
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2008年4月 - 2013年3月
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2007年4月 - 2008年3月
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1995年4月 - 1998年3月
学歴
2-
1998年4月 - 2002年3月
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1989年4月 - 1995年3月
論文
132-
Allergology international : official journal of the Japanese Society of Allergology 73(1) 174-176 2024年1月
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PNAS Nexus 2023年12月21日 査読有り
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Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 19(1) 42-42 2023年5月16日BACKGROUND: Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein-kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE. CASE PRESENTATION: Here we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT. CONCLUSIONS: This case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.
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Journal of the American Society of Nephrology : JASN 2023年5月3日 査読有り最終著者責任著者BACKGROUND: Nuclear translocation of dendrin is observed in the glomeruli in numerous human renal diseases, but the mechanism remains unknown. This study investigated that mechanism and its consequence in podocytes. METHODS: The effect of dendrin deficiency was studied in adriamycin (ADR)- nephropathy model and membrane-associated guanylate kinase inverted 2 ( MAGI2) podocyte-specific knockout ( MAGI2 podKO) mice. The mechanism and the effect of nuclear translocation of dendrin were studied in podocytes overexpressing (OE) full-length dendrin and nuclear localization signal 1 (NLS1)- deleted dendrin. Ivermectin was used to inhibit importin-α. RESULTS: Dendrin ablation reduced albuminuria, podocyte loss, and glomerulosclerosis in ADR-induced nephropathy and MAGI2 podKO mice. Dendrin deficiency also prolonged the lifespan of MAGI2 podKO mice. Nuclear dendrin promoted JNK phosphorylation that subsequently altered focal adhesion, reducing cell attachment and enhancing apoptosis in cultured podocytes. Classical bipartite NLS sequence and importin-α mediate nuclear translocation of dendrin. The inhibition of importin-α/β reduced dendrin nuclear translocation and apoptosis in vitro as well as albuminuria, podocyte loss, and glomerulosclerosis in ADR-induced nephropathy and MAGI2 podKO mice. Importin-α3 colocalized with nuclear dendrin in the glomeruli of focal segmental glomerulosclerosis and IgA nephropathy patients. CONCLUSION: Nuclear translocation of dendrin promotes cell detachment-induced apoptosis in podocytes. Therefore, inhibiting importin-α-mediated dendrin nuclear translocation is a potential strategy to prevent podocyte loss and glomerulosclerosis.
MISC
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NEPHROLOGY DIALYSIS TRANSPLANTATION 33 55-55 2018年5月
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MICROVASCULAR RESEARCH 110 65-65 2017年3月
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Nephrology Frontier 13(1) 96-103 2014年3月保存期慢性腎臓病患者におけるAST-120(クレメジン)服薬サポートプログラムの効果について検討した。慢性腎臓病(CKD)の診断で現在AST-120(クレメジン)を服用している、あるいはCKDの診断で初めてAST-120を服用する22例を対象とした。開始時と終了時の腎機能には変化がなかったが、観察期間での服薬率良好群と不良群では腎機能の低下に明らかな差を認めた。通院期間やこれまでのAST-120服用期間が長い症例群で服薬良好群が多い傾向であった。さらに、患者サポートプログラムによってCKD理解が向上した群では、服薬良好群が占める割合が多かった。診療によって繰り返しCKDの情報を受けた患者やAST-120の薬効などの情報を受けた患者が服薬アドヒアランスの高い患者群であるだけでなく、集中的に疾患並びに服薬の重要性、服薬に関わる情報を提供することで同様の効果が得られる可能性が示された。
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PEDIATRIC NEPHROLOGY 28(8) 1438-1439 2013年8月 査読有り
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AUTOPHAGY 8(4) 445-544 2012年4月In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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JOURNAL OF CLINICAL INVESTIGATION 122(2) 781-781 2012年2月
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順天堂医学 = Juntendo medical journal 57(5) 488-493 2011年10月31日
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Therapeutic Research 31(10) 1471-1480 2010年10月高カリウム血症を伴う慢性腎臓病患者55例を対象に、ポリスチレンスルホン酸カルシウム(PS-Ca)ゼリーを6ヵ月以上投与し、その効果を検討した。その結果、PS-Caゼリーは10ヵ月間にわたり有意で安定した血清カリウム値の低下が得られることが確認された。その低下作用は用量依存性で、血清カリウム低下量はPS-Caゼリー1個/日で0.65mEq/L、2個/日で0.84mEq/L、3個/日で1.00mEq/Lであった。また、PS-CaゼリーはRAAS抑制薬使用の有無にかかわらず、血清カリウム値を有意に低下した。一方、血清カリウム値の変化量で比較すると、RAAS抑制薬使用症例の方が低下の程度は大きかったが、PS-Caゼリーは血清カリウム以外の血清電解質に対する影響はなく、副作用も試験期間中に認められなかった。以上、これらのことからも、高カリウム血症を伴う慢性腎臓病患者に対するPS-Caゼリーの長期投与の効果が確認された。
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NITRIC OXIDE-BIOLOGY AND CHEMISTRY 22 S74-S75 2010年6月
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日本透析医学会雑誌 42(11) 899-904 2009年11月症例は34歳男性で、劣性栄養障害型表皮水疱症で通院中に腎機能障害となった。顔面浮腫、四肢全身に多発する表皮剥離・水疱、両手足の棍棒状変形を認めた。血液生化学検査では高度な貧血、低蛋白、電解質異常を認め、慢性的な炎症性変化によると思われる鉄の利用障害を認めた。特殊検査では血清アミロイドA蛋白、iPTH、hANP高値を認めた。動脈血液ガス分析では低酸素血症を認め、胸部X線で両側に胸水を認めた。腎機能悪化、鬱血性心不全、高度な貧血を認めたことから緊急的に右内頸動脈よりダブルルーメンカテーテルを挿入し、続発性アミロイドーシスによると考え血液透析を施行した。末期腎不全(EKSD)を合併した劣性栄養障害型表皮水疱症で長期留置型カテーテルを用い、血液透析を導入し、維持透析に移行することができた。先天性表皮水疱症は軽微な機械的な刺激により表皮下水疱や糜爛を生じるため腹膜透析や内シャントを造設すること、シャントの穿刺・止血が困難で透析療法やバスキュラーアクセスの選択には検討が必要と思われた。
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順天堂医学 54(2) 230-230 2008年6月
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NEPHROLOGY 13 A28-A28 2008年5月
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NEPHROLOGY 12 S15-S20 2007年12月Glomerular visceral epithelial cells, also known as podocytes, are highly specialized epithelial cells that cover the outer layer of the glomerular basement membrane. Podocytes consist of cell bodies, major processes and foot processes (FP) of neighbouring cells, with the filtration slits bridged by the slit membrane between them. The function of podocytes is largely based on their specialized cell architecture and functions such as stabilization of glomerular capillaries and participation in the barrier function of the glomerular filter. Therefore, they form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Under pathological conditions, podocytes exhibit various changes. Among these changes, FP effacement represents the most characteristic change in cell shape of podocytes. FP effacement is dependent on disruption of the actin cytoskeletal network in the podocytes, The mechanisms of organization and re-organization of actin in the FP of podocytes are discussed in this review.
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TRENDS IN CELL BIOLOGY 17(9) 428-437 2007年9月Podocytes of the renal glomerulus are unique cells with a complex cellular organization consisting of a cell body, major processes and foot processes. Podocyte foot processes form a characteristic interdigitating pattern with foot processes of neighboring podocytes, leaving in between the filtration slits that are bridged by the glomerular slit diaphragm. The highly dynamic foot processes contain an actin-based contractile apparatus comparable to that of smooth muscle cells or pericytes. Mutations affecting several podocyte proteins lead to rearrangement of the actin cytoskeleton, disruption of the filtration barrier and subsequent renal disease. The fact that the dynamic regulation of the podocyte cytoskeleton is vital to kidney function has led to podocytes emerging as an excellent model system for studying actin cytoskeleton dynamics in a physiological context.
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AMERICAN JOURNAL OF PATHOLOGY 171(2) 415-427 2007年8月The actin-based foot processes of kidney podocytes and the interposed slit diaphragm form the final barrier to proteinuria. Mutations affecting several podocyte proteins cause disruption of the filtration barrier and rearrangement of the highly dynamic podocyte actin cytoskeleton. Proteins regulating the plasticity of the podocyte actin cytoskeleton are therefore of critical importance for sustained kidney barrier function. Synaptopodin is an actin-associated protein essential for the integrity of the podocyte actin cytoskeleton because synaptopodin-deficient mice display impaired recovery from protamine sulfate-induced foot process effacement and lipopolysaccharide-induced nephrotic syndrome. Moreover, bigenic heterozygosity for synaptopodin and CD2AP is sufficient to induce spontaneous proteinuria and focal segmental glomerulosclerosis-like glomerular damage in mice. Mechanistically, synaptopodin induces stress fibers by blocking the proteasomal degradation of RhoA. Here we show that synaptopodin directly binds to IRSP53 and suppresses Cdc42:IRSp53:Mena-initiated filopodia formation by blocking the binding of Cdc42 and Mena to IRSp53. The Mena inhibitor FP4- Mito suppresses aberrant filopodia formation in synaptopodin knockdown podocytes, and when delivered into mice protects against lipopolysaccharide-induced proteinuria. The identification of synaptopodin as an inhibitor of Cdc42:IRSp53:Mena signaling defines a novel antiproteinuric signaling pathway and offers new targets for the development of antiproteinuric therapeutic modalities.
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 104(24) 10134-10139 2007年6月Kidney podocytes and their slit diaphragms (SDs) form the final barrier to urinary protein loss. There is mounting evidence that SD proteins also participate in intracellular signaling pathways. The SD protein nephrin serves as a component of a signaling complex that directly links podocyte junctional integrity to actin cytoskeletal dynamics. Another SD protein, CD2-associated protein (CD2AP), is an adaptor molecule involved in podocyte homeostasis that can repress proapoptotic TGF-ss signaling in podocytes. Here we show that dendrin, a protein originally identified in telencephalic dendrites, is a constituent of the SD complex, where it directly binds to nephrin and CD2AP. In experimental glomerulonephritis, dendrin relocates from the SD to the nucleus of injured podocytes. High-dose, proapoptotic TGF-ss 1 directly promotes the nuclear import of dendrin, and nuclear dendrin enhances both staurosporine- and TGF-ss 1-mediated apoptosis. In summary, our results identify dendrin as an SD protein with proapoptotic signaling properties that accumulates in the podocyte nucleus in response to glomerular injury and provides a molecular target to tackle proteinuric kidney diseases. Nuclear relocation of dendrin may provide a mechanism whereby changes in SD integrity could translate into alterations of podocyte survival under pathological conditions.
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JOURNAL OF CLINICAL INVESTIGATION 116(5) 1337-1345 2006年5月Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, alpha-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease.
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NATURE CELL BIOLOGY 8(5) 485-U109 2006年5月The Rho family of small GTPases (RhoA, Rac1 and Cdc42) controls signal-transduction pathways that influence many aspects of cell behaviour, including cytoskeletal dynamics(1-3). At the leading edge, Rac1 and Cdc42 promote cell motility through the formation of lamellipodia and filopodia, respectively. On the contrary, RhoA promotes the formation of contractile actin-myosin-containing stress fibres in the cell body and at the rear(1,2,4). Here, we identify synaptopodin, an actin-associated protein, as a novel regulator of RhoA signalling and cell migration in kidney podocytes. We show that synaptopodin induces stress fibres by competitive blocking of Smurf1-mediated ubiquitination of RhoA, thereby preventing the targeting of RhoA for proteasomal degradation. Gene silencing of synaptopodin in kidney podocytes causes the loss of stress fibres and the formation of aberrant non-polarized filopodia and impairment of cell migration. Together, these data show that synaptopodin is essential for the integrity of the podocyte actin cytoskeleton and for the regulation of podocyte cell migration.
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JOURNAL OF CLINICAL INVESTIGATION 115(5) 1188-1198 2005年5月Synaptopodin is the founding member of a novel class of proline-rich actin-associated proteins highly expressed in telencephalic dendrites and renal podocytes. Synaptopodin-deficient (synpo(-/-)) mice lack the dendritic spine apparatus and display impaired activity-dependent long-term synaptic plasticity. In contrast, the ultrastructure of podocytes in synpo(-/-) mice is normal. Here we show that synpo(-/-) mice display impaired recovery from protamine sulfate-induced podocyte foot process (FP) effacement and LPS-induced nephrotic syndrome. Similarly, synpo(-/-) podocytes show impaired actin filament reformation in vitro. We further demonstrate that synaptopodin exists in 3 isoforms, neuronal Synpo-short (685 AA), renal Synpo-long (903 AA), and Synpo-T (181 AA). The C terminus of Synpo-long is identical to that of Synpo-T. All 3 isoforms specifically interact with a-actinin and elongate alpha-actinin-induced actin filaments. synpo(-/-) mice lack Synpo-short and Synpo-long expression but show an upregulation of Synpo-T protein expression in podocytes, though not in the brain. Gene silencing of Synpo-T abrogates stress-fiber formation in synpo(-/-) podocytes, demonstrating that Synpo-T serves as a backup for Synpo-long in synpo(-/-) podocytes. In concert, synaptopodin regulates the actin-bundling activity of a-actinin in highly dynamic cell compartments, such as podocyte FPs and the dendritic spine apparatus.
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JOURNAL OF BIOLOGICAL CHEMISTRY 279(33) 34827-34832 2004年8月Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and alpha(3) integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking alpha(3) integrin. Similarly, acute functional inhibition of alpha(3) integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Downregulation of alpha(3) integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and alpha(3) integrin.
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JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY 52(5) 683-691 2004年5月Glomerular expression of tensin was immunohistochemically studied in normal and diseased rat kidneys to determine whether tensin might be related to specific binding in individual glomerular cells. Normal rat kidneys displayed an intense immunofluorescence reaction for tensin along the basal aspects of proximal and distal tubule cells and parietal epithelial cells of Bowman's capsules. in glomeruli, a positive reaction for tensin was detected only in the mesangial areas. Immunoelectron microscopy revealed a positive reaction in the mesangial cell (MC) processes. RT-PCR and immunoprecipitation demonstrated mRNA and protein levels of tensin in cultured rat MCs. Mesangial tensin expression was decreased when the mesangium was injured by Habu snake venom. During the regenerative process after mesangiolysis, tensin expression was not detected in early-phase proliferating MCs that did not have extracellular matrix (ECM). The expression of tensin recovered in late-phase proliferating MCs, which became attached to regenerated ECM. It appears that tensin is related to MC attachment to surrounding ECM, which suggests that signal transduction regulated by tensin may be related to a specific mechanism of MC matrix regeneration. Furthermore, tensin can act as a marker for rat MCs because the expression of tensin was detected only in MCs in glomeruli.
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JOURNAL OF CLINICAL INVESTIGATION 113(10) 1390-1397 2004年5月Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.
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HISTOCHEMISTRY AND CELL BIOLOGY 121(3) 245-254 2004年3月Tensin, a focal adhesion protein, is expressed in renal tubular epithelial cells (TECs). Tensin-null mice develop multiple large cysts in the renal proximal tubules. However, the role of tensin in human glomeruli remains unclear. In this study, we assessed tensin localization in human kidney and interaction between tensin and other adhesion components. In human mesangial cells (MCs) and TECs, we confirmed mRNA and protein expressions of tensin by RT-PCR and immunoprecipitation. In normal kidney, immunohistochemistry revealed that tensin was localized in MCs and parietal epithelial cells as well as TECs. In biopsy specimens, the expression of tensin was significantly increased in areas of mesangial expansion in patients with IgA nephropathy and diabetic nephropathy. These results suggest that the expression of tensin is associated with extracellular matrix (ECM) production. In vitro, immunocytochemistry revealed that MCs express tensin mainly at the ends of actin stress fibers and apparently in the focal adhesion areas. Integrin alpha5, but not alpha1 and alpha3, colocalized with tensin. Vinculin and focal adhesion kinase (FAK) were coprecipitated by tensin, suggesting that tensin can mediate signal transduction between cell and ECM through these molecules. Tensin may play important roles in mesangial ECM production through an adhesion complex with integrin alpha5, FAK, and vinculin.
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Clinical and Experimental Nephrology 7(4) 255-259 2003年12月Podocytes are unique cells with a complex cellular organization. With respect to their cytoarchitecture, podocytes may be divided into three structurally and functionally different segments: cell body, major processes, and foot processes (FPs). The FPs of neighboring podocytes regularly interdigitate, leaving between them the filtration slits that are bridged by an extracellular structure, known as the slit diaphragm (SD). Podocytes cover the outer aspect of the glomerular basement membrane (GBM). They therefore form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Chronic podocyte injury may lead to podocyte detachment from the GBM. Our knowledge of the molecular structure of the SD has been remarkably improved in the past few years. Several molecules, including nephrin, CD2AP, FAT, ZO-1, P-cadherin, Podocin, and Neph 1-3 have all been shown to be associated with the SD complex, and some of these molecules are critical for its integrity. Podocytes are injured in many forms of human and experimental glomerular disease. The early events are characterized either by alterations in the molecular composition of the SD without visible changes in morphology or, more obviously, by a reorganization of FP structure with the fusion of filtration slits and the apical displacement of the SD. Based on recent insights into the molecular pathology of podocyte injury, at least four major causes have been identified that lead to the uniform reaction of FP effacement and proteinuria: (1) interference with the SD complex and its lipid rafts (2) direct interference with the actin cytoskeleton (3) interference with the GBM or with podocyte-GBM interaction and (4) interference with the negative surface charge of podocytes. There is also evidence, in focal segmental glomerular sclerosis (FSGS) and in idiopathic nephrotic syndrome in humans and rats, that podocyte damage may be caused by circulating albuminuric factors. Ongoing studies in many laboratories are aiming at an understanding of the dynamic relationship between SD proteins, the actin cytoskeleton, and the dynamics of FP structure in nephrotic syndrome and FSGS. These studies should provide us with a better understanding of the biological mechanism underlying the podocyte response to injury. Such studies will potentially translate into more refined treatment and the prevention of proteinuria and progressive glomerular disease.
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JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 59A-59A 2003年11月
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FASEB JOURNAL 17(6) 1165-+ 2003年4月Microtubule-associated protein 1 light chain 3 (LC3) is a unique modifier protein. LC3-I, the cytosolic form, is modified to LC3-II, the membrane-bound form, by a mechanism similar to ubiquitylation by E1- and E2-like enzymes, Apg7p and Apg3p, respectively. In the present study, we found that LC3-I is processed to LC3-II during the differentiation and recovery from puromycin aminonucleoside-induced nephrosis of podocytes. LC3 is especially expressed in the podocytes of rat kidney as the membrane-bound form LC3-II. Biochemical analysis using a conditionally immortalized mouse podocyte clone (MPC) revealed that LC3-I is processed to LC3-II during the differentiation of cells into mature podocytes and accumulates in the membrane-rich fraction of the cell lysate. LC3-II-localized vesicles, which differ from lysosomes and endosomes, in differentiated MPC cells are morphologically similar to autophagic vacuoles during starvation-induced autophagy. During starvation-induced autophagy, autophagosomes fuses with lysosome and LC3-II on autophagosomes is finally degraded by lysosomal proteases. However, in differentiated MPC cells, little LC3-II on the vesicles is degraded by lysosomal proteases, suggesting that little LC3-II-localized vesicles in differentiated MPC cells fuse with lysosome. Furthermore, the LC3-II level in differentiated MPC cells increases with recovery from damage caused by experimental puromycin aminonucleoside-induced nephrosis. These results suggest that LC3-II-localized vesicles play an important role in the physiological function of podocytes.
講演・口頭発表等
10担当経験のある科目(授業)
1-
腎臓内科学 (千葉大学)
共同研究・競争的資金等の研究課題
18-
日本学術振興会 科学研究費助成事業 基盤研究(B) 2023年4月 - 2026年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2020年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2018年4月 - 2021年3月
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科学研究費補助金(挑戦的萌芽研究) 2017年 - 2018年
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科学研究費補助金(挑戦的萌芽研究) 2014年 - 2016年