Common pathogenesis of nephrotic syndrome and vascular diseases in other organs

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390224
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Niigata University
• Principal Investigator: KAWACHI HIROSHI 新潟大学, 医歯学系, 教授 (60242400)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Kenji 新潟大学, 医歯学総合病院, 講師 (00303123) ; MATSUI Katsuki 帝京大学, 医学部, 教授 (20256027) ; WATANABE Kenichi 新潟薬科大学, 薬学部, 教授 (70175090) ; IKEZUMI Yohei 新潟大学, 医歯学総合病院, 講師 (70361897)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 蛋白尿 / 細胞間接着装置 / 心腎連関 / ネフローゼ症候群 / 慢性腎臓病 / ポドサイト

Research Abstract

We have identified Ephrin-B1 and SV2B as molecules of which dysfunction is involved in the development of nephrotic syndrome and neuronal and vascular diseases. In this study we analyzed the expression and function of these molecules with several experimental models and knockout mice. This study revealed that ephrin-B1 was localized at the surface of podocyte and bound to nephrin, a critical molecule of the slit diaphragm. SV2B (synaptic vesicle protein 2B), which is expressed on the surface of synaptic vesicles in neuron, was localized at the slit diaphragm area in podocyte and played an essential role in maintaining the structure of foot process, slit diaphragm and GBM. SV2B KO mice showed proteinuria. The altered expression of the slit diaphragm molecules including CD2AP and nephrin was detected in KO mice. These observations provide important information to understand the common pathogenesis of nephrotic syndrome and other diseases.

Research Products

• [Journal Article] Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury (2014)
  • Author(s): Yamada S, Nakamura J, Asada M, Takase M, Matsusaka T, Iguchi T, Yamada R, Tanaka M, Higashi AY, Okuda T, Asada N, Fukatsu A, Kawachi H, Graf D, Muso E, Kita T, Kimura T, Pastan I, Economides AN, Yanagita M
  • Journal Title: PLoS One Volume: 9(2)(印刷中) Pages: 25
  • DOI: 10.1371/journal.pone.0089135
  • Peer Reviewed
• [Journal Article] Therapeutic target for nephrotic syndrome : Identification of novel slit diaphragm associated molecules (2014)
  • Author(s): Y. Fukusumi, N. Miyauchi, T. Hashimoto, A Saito and H. Kawachi
  • Journal Title: World journal of World journal of Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] 糸球体性蛋白尿の発症機序 (2014)
  • Author(s): 河内裕, 福住好恭
  • Journal Title: Medicina Volume: vol. 51, No. 8(印刷中)
• [Journal Article] 糸球体濾過障壁と蛋白尿 (2014)
  • Author(s): 河内裕
  • Journal Title: 腎と透析 Volume: 76
• [Journal Article] Tyrosine kinases inhibition by Imatinib slows progression in chronic anti-thy1 glomerulosclerosis of the rat (2013)
  • Author(s): Wang-Rosenke Y, Khadzhynov D, Loof T, Mika A, Kawachi H, Neumayer HH, Peters H
  • Journal Title: BMC Nephrol Volume: 14 : 14
  • DOI: 10.1186/1471-2369-14-223
  • Peer Reviewed
• [Journal Article] Planar cell polarity pathway regulates nephrin endocytosis in developing podocytes (2013)
  • Author(s): Babayeva S, Rocque B, Aoudjit L, Zilber Y, Li J, Baldwin C, Kawachi H, Takano T, Torban E
  • Journal Title: J Biol Chem Volume: 16;288(33) Pages: 24035-48
  • Peer Reviewed
• [Journal Article] The hyperglycemia stimulated myo-cardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats : a differential role of unfolded protein response (UPR) signaling proteins (2013)
  • Author(s): Lakshmanan AP, Harima M, Suzuki K, Soetikno V, Nagata M, Nakamura T, Takahashi T, Sone H, Kawachi H, Watanabe K
  • Journal Title: Int J Biochem Cell Biol Volume: 45 Pages: 438-447
  • DOI: 10.1016/j.biocel.2012.09.017
  • Peer Reviewed
• [Journal Article] 腎糸球体上皮細胞(ポドサイト)スリット膜の構造と機能-ARBのポドサイト保護作用 (2013)
  • Author(s): 河内裕, 高橋彩, 山崎美穂子, 福住好恭, 富田雅之
  • Journal Title: Pharma Medica Volume: 31 Pages: 98-100
• [Journal Article] Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway (2012)
  • Author(s): Soetikno V, Sari FR, Lakshmanan AP, Arumugam S, Harima M, Suzuki K, Kawachi H, Watanabe K
  • Journal Title: Mol Nutr Food Res Volume: 57 Pages: 1649-1659
  • DOI: 10.1002/mnfr.201200540
  • Peer Reviewed
• [Journal Article] Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats (2012)
  • Author(s): Soetikno V, Sari FR, Sukumaran V, Lakshmanan AP, Harima M, Suzuki K, Kawachi H, Watanabe K
  • Journal Title: J Nutr Biochem Volume: 24 Pages: 796-802
  • DOI: 10.1016/j.jnutbio.2012.04.013
  • Peer Reviewed
• [Journal Article] Irsogladine maleate ameliorates inflammation and fibrosis in mice with chronic colitis induced by dextran sulfate sodium (2012)
  • Author(s): Yamaguchi H, Suzuki K, Nagata M, Kawase T, Sukumaran V, Thandavarayan RA, Kawauchi Y, Yokoyama J, Tomita M, Kawachi H, Watanabe K, Yoneyama H, Asakura H, Takagi R
  • Journal Title: Med Mol Morphol Volume: 45 Pages: 140-151
  • Peer Reviewed
• [Journal Article] Early treatment with everolimus exerts nephroprotective effect in rats with adriamycin-induced nephropathy (2012)
  • Author(s): Ramadan R, Faour D, Awad H, Khateeb E, Cohen R, Yahia A, Torgovicky R, Cohen R, Lazari D, Kawachi H, Abassi Z
  • Journal Title: Nephrol Dial Transplant Volume: 27 Pages: 2231-2241
  • DOI: 10.1093/ndt/gfr581
  • Peer Reviewed
• [Journal Article] Development of lymphatic vasculature and morphological characterization in rat kidney (2012)
  • Author(s): Tanabe M, Shimizu A, Masuda Y, Kataoka M, Ishikawa A, Wakamatsu K, Mii A, Fujita E, Higo S, Kaneko T, Kawachi H, Fukuda Y
  • Journal Title: Clin Exp Nephrol Volume: 16 Pages: 833-842
  • DOI: 10.1007/s10157-012-0637-z
  • Peer Reviewed
• [Journal Article] Early treatment with olmesartan prevents juxtamedullary glomerular podocyte injury and the onset of microalbuminuria in type 2 diabetic rats (2012)
  • Author(s): Sofue T, Kiyomoto H, Kobori H, Urushihara M, Nishijima Y, Kaifu K, Hara T, Matsumoto S, Ichimura A, Ohsaki H, Hitomi H, Kawachi H, Hayden MR, Whaley-Connell A, Sowers JR, Ito S, Kohno M, Nishiyama A
  • Journal Title: Am J Hypertens Volume: 25(5) Pages: 604-11
  • DOI: 10.1038/ajh.2012.1
  • Peer Reviewed
• [Journal Article] Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis (2012)
  • Author(s): Sato A, Piao H, Nozawa Y, Morioka T, Kawachi H, Oite T
  • Journal Title: Clin Exp Nephrol Volume: 16 Pages: 539-48
  • DOI: 10.1007/s10157-012-0601-y
  • Peer Reviewed
• [Journal Article] Proteinuria in AMPD2-deficient mice (2012)
  • Author(s): Toyama K, Morisaki H, Cheng J, Kawachi H, Shimizu F, Ikawa M, Okabe M, Morisaki T
  • Journal Title: Genes Cells Volume: 17 Pages: 28-38
  • DOI: 10.1111/j.1365-2443.2011.01568.x
  • Peer Reviewed
• [Journal Article] Angiotensin II type I receptor blockade suppresses glomerular renin-angiotensin system activation, oxidative stress, and progressive glomerular injury in rat anti-glomerular basement membrane glomerulonephritis (2012)
  • Author(s): Kinoshita Y, Kondo S, Urushihara M, Suga K, Matsuura S, Takamatsu M, Shimizu M, Nishiyama A, Kawachi H, Kagami S
  • Journal Title: Transl Res Volume: 158 Pages: 235-48
  • DOI: 10.1016/j.trsl.2011.05.003
  • Peer Reviewed
• [Journal Article] Curcumin ameliorates macrophage infiltration by inhibiting NF-κ B activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy (2011)
  • Author(s): Soetikno V, Sari FR, Veeraveedu PT, Thandavarayan RA, Harima M, Sukumaran V, Lakshmanan AP, Suzuki K, Kawachi H, Watanabe K
  • Journal Title: Nutr Metab (Lond) Volume: 8 Pages: 35
  • DOI: 10.1186/1743-7075-8-35
  • Peer Reviewed
• [Journal Article] Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium (2011)
  • Author(s): Suzuki K, Sun X, Nagata M, Kawase T, Yamaguchi H, Sukumaran V, Kawauchi Y, Kawachi H, Nishino T, Watanabe K, Yoneyama H, Asakura H
  • Journal Title: Pathol Int Volume: 61 Pages: 228-238
  • DOI: 10.1111/j.1440-1827.2011.02647.x
  • Peer Reviewed
• [Journal Article] Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy : potential role in mesangial matrix expansion (2011)
  • Author(s): Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Yamada T, Imai N, Narita I, Kawachi H, Polkinghorne KR, Nikolic-Paterson DJ, Uchiyama M
  • Journal Title: Histopathology Volume: 58 Pages: 198-210
  • DOI: 10.1111/j.1365-2559.2011.03742.x
  • Peer Reviewed
• [Journal Article] Neurexin-1, a presynatic adhesion molecule, localizes at the slit diaphragm of the glomerular podocytes in kidneys (2011)
  • Author(s): Saito A, Miyauchi N, Hashimoto T, Karasawa T, Han GD, Kayaba M, Sumi T, Tomita M, Ikezumi Y, Suzuki K, Koitabashi Y, Shimizu F, Kawachi H
  • Journal Title: Am J Physiol Regulatory Integrative Comparative Physiology Volume: 300 Pages: R340-R348
  • DOI: 10.1152/ajpregu.00640.2009
  • Peer Reviewed
• [Journal Article] A notable case report of May-Hegglin anomaly with immune complex-related nephropathy : a genetic and histological analysis (2011)
  • Author(s): Ohtsuka Y, Kanaji T, Nishi M, Sakai N, Sato T, Aoki S, Wakayama K, Nakazato S, Hisano S, Sado Y, Kawachi H, Izuhara K, Hamasaki Y
  • Journal Title: Clin Nephrol Volume: 75 Pages: 255-262
  • DOI: 10.5414/CNP75255
  • Peer Reviewed
• [Journal Article] Defective glycosylation of α -dystroglycan contributes to podocyte flattening (2011)
  • Author(s): Kojima K, Nosaka H, Kishimoto Y, Nishiyama Y, Fukuda S, Shimada M, Kodaka K, Saito F, Matsumura K, Shimizu T, Toda T, Takeda S, Kawachi H, Uchida S
  • Journal Title: Kidney Int Volume: 79 Pages: 311-316
  • DOI: 10.1038/ki.2010.403
  • Peer Reviewed
• [Journal Article] CD28 superagonist-induced regulatory T cell expansion ameliorates mesangio proliferative glomerulo- nephritis in rats (2011)
  • Author(s): Miyasato K, Takabatake Y, Kaimori J, Kimura T, Kitamura H, Kawachi H, Li XK, Hünig T, Takahara S, Rakugi H, Isaka Y
  • Journal Title: Clin Exp Nephrol Volume: 15 Pages: 50-57
  • DOI: 10.1007/s10157-010-0370-4
  • Peer Reviewed
• [Journal Article] 膜性腎症(特発性膜性腎症) (2011)
  • Author(s): 河内裕, 長田道夫
  • Journal Title: 腎臓 Volume: 33 Pages: 227-231
• [Journal Article] ループス腎炎モデル (2011)
  • Author(s): 長田道夫, 河内裕
  • Journal Title: 腎臓 Volume: 34 Pages: 48-53
• [Presentation] シナプス小胞分子SV2BKOマウス腎におけるシナプス小胞様輸送関連分子の発現解析 (2014)
  • Author(s): 福住好恭
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜, 神奈川
  • Year and Date: 20140704-06
• [Presentation] Calcineurin (CN)阻害薬はスリット膜保護作用により蛋白尿を改善する (2014)
  • Author(s): 若松彩子
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜, 神奈川
  • Year and Date: 20140704-06
• [Presentation] 各種ポドサイト機能分子の病勢診断マーカーとしての有用性の検討 : ラットPAN腎症モデルを用いた解析 (2014)
  • Author(s): 金子博司
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜, 神奈川
  • Year and Date: 20140704-06
• [Presentation] Synaptic vesicle protein 2B is essential for the maintenance of the integrity of the silt diaphragm (2014)
  • Author(s): 福住好恭
  • Organizer: 第10回国際ポドサイト学会
  • Place of Presentation: フライブルグ, ドイツ
  • Year and Date: 20140604-06
• [Presentation] Rituximab Ameliorates Proteinuria in Rat Adriamycin Nephropathy Independently with Its Action to B Lymphocyte (2013)
  • Author(s): Takahashi Y
  • Organizer: 第46回アメリカ腎臓学会総会
  • Place of Presentation: アトランタ, アメリカ
  • Year and Date: 20131105-10
• [Presentation] Calcineurin Is Mainly Localized at the Slit Diaphragm Area, and Its Altered Expression Precedes Proteinuria in Rat Nephrotic Syndrome Models (2013)
  • Author(s): Wakamatsu A
  • Organizer: 第46回アメリカ腎臓学会総会
  • Place of Presentation: アトランタ, アメリカ
  • Year and Date: 20131105-10
• [Presentation] Synaptic Vesicle Protein 2B Is Essential for Maintaining the Integrity of the Podocyte Slit Diaphragm; SV2B KO Mice Are Vulnerable to the Podocyte Injury (2013)
  • Author(s): Fukusumi Y
  • Organizer: 第46回アメリカ腎臓学会総会
  • Place of Presentation: アトランタ, アメリカ
  • Year and Date: 20131105-10
• [Presentation] Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury (2013)
  • Author(s): Yanagita M
  • Organizer: 第46回アメリカ腎臓学会総会
  • Place of Presentation: アトランタ, アメリカ
  • Year and Date: 20131105-10
• [Presentation] Glomerular expression of Renin-Angiotensin system components in Rats with podocyte dysfunction (2012)
  • Author(s): Yamazaki Y
  • Organizer: 第45回アメリカ腎臓学会総会
  • Place of Presentation: サンディエゴ, アメリカ
  • Year and Date: 20121030-1104
• [Presentation] Role of p38 MAPK activation in the slit diaphragm dysfunction and proteinuria caused by a direct stimulation to nephrin (2012)
  • Author(s): Takahashi Y
  • Organizer: 第45回アメリカ腎臓学会総会
  • Place of Presentation: サンディエゴ, アメリカ
  • Year and Date: 20121030-1104
• [Presentation] Ephrin-B is interacted with nephrin and plays an important role in the slit diaphragm. - Decreased expression of ephrin-B is an early marker to detect slit diaphragm dysfunction- (2012)
  • Author(s): Tomita M
  • Organizer: 9th International Podocyte Conference
  • Place of Presentation: Miami Beach Resort & Spa マイアミ, アメリカ
  • Year and Date: 20120422-25
• [Presentation] Ephrin‐ B1 in podocyte is interacted with nephrin and is phosphrylated by a signal from nephrin (2011)
  • Author(s): Murad H
  • Organizer: 第44回アメ リカ腎臓学会総会
  • Place of Presentation: フィラデルフィア, アメリカ
  • Year and Date: 20111110-13
• [Presentation] Ephrin-B1 is expressed at the slit diaphragm and is struturally and functionally interacted with nephrin (2011)
  • Author(s): Murad H
  • Organizer: 国際腎臓学会(ISN) Forefront Symposium
  • Place of Presentation: オーフス, デンマーク
  • Year and Date: 20110922-25
• [Book] 小児腎臓病学 (2011)
  • Author(s): 河内裕
  • Total Pages: 94-98
  • Publisher: 診断と治療社
• [Book] 腎臓症候群 (2011)
  • Author(s): 河内裕
  • Total Pages: 93-96
  • Publisher: 日本臨床社
• [Remarks]
  • URL: http://www.med.niigata-u.ac.jp/nim/welcomej.html