glomerular sclerosis

• Project/Area Number: 16109005
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Kidney internal medicine
• Research Institution: Tokai University
• Principal Investigator: ICHIKAWA Iekuni Tokai University, 医学部, 教授 (80317768)
• Co-Investigator(Kenkyū-buntansha): MATSUSAKA Taiji 東海大学, 医学部, 准教授 (50317749) ; NIIMURA Fumio 東海大学, 医学部, 准教授 (30282750) ; NAGATA Michio 筑波大学, 基礎医学系, 教授 (10192238)
• Co-Investigator(Renkei-kenkyūsha): MOTOJIMA Masaru 東海大学, 医学部, 講師 (80468636)
• Project Period (FY): 2004 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥107,380,000 (Direct Cost: ¥82,600,000、Indirect Cost: ¥24,780,000); Fiscal Year 2008: ¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000); Fiscal Year 2007: ¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000); Fiscal Year 2006: ¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000); Fiscal Year 2005: ¥20,930,000 (Direct Cost: ¥16,100,000、Indirect Cost: ¥4,830,000); Fiscal Year 2004: ¥22,100,000 (Direct Cost: ¥17,000,000、Indirect Cost: ¥5,100,000)
• Keywords: ポドサイト / 慢性腎不全 / 細胞周期 / レニン・アンギオテンシン / 糸球体硬化症 / 蛋白尿 / Angiotensin II / SV40 / megalin / トランスジェニックマウス / キメラマウス / GIV-1 / 糸球体上皮細胞 / ノックアウトマウス / Cre-loxPシステム / Megalin / VEGF / SV40T / コンディショナル・ターゲッティング

Research Abstract

慢性腎臓病は国民健康上の大きな問題であるが、腎臓のポドサイトという細胞の傷害が鍵になっている。ポドサイトは生後に増殖する事なく、一度失われると補充される事はない。我々は、ポドサイトの増加を新たな治療の方向性として、生体内でポドサイトの増殖を誘導させる実験を行った。その結果、ポドサイトの増殖は、脱分化とは不可分ではなく、可能である事を示した。また、多くの腎臓病において、ポドサイトの傷害の後、尿細管傷害が続発するが、その過程において、megalin によるタンパク質の再吸収が関与する事を明らかにした。さらに、Angiotensin II が腎臓病を増悪させるが、その機序を明らかにし、またAngiotensin の産生経路に新たな発見を得た。

Research Products

• [Journal Article] Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Prietal Cell Hyperplasia in a Murine Model of Celluar/Collapsing Focal Segmental Glomerulosclerosis. (2009)
  • Author(s): Suzuki T, Matsusaka T, Nakayama M, Asano T, Watanabe T, Ichikawa I, Nagata M.
  • Journal Title: Am J Pathol. 174(5) : (in press)
  • Peer Reviewed
• [Journal Article] Fibrinogen That Appear in the Bowman's Space of Proteinuric Kidneys in vivo Activates Podocyte Toll-like Receptor 2 and 4 in vitro. (2009)
  • Author(s): Motojima M, Matsusaka T, Kon V, Ichikawa I.
  • Journal Title: Nephron Experimental. (in press)
  • Peer Reviewed
• [Journal Article] An essential role of the universal polarity protein, aPKClambda, on the maintenance of podocyte slit diaphragms (2009)
  • Author(s): Hirose T, Satoh D, Kurihara H, Kusaka C, Hirose H, Akimoto K, Matsusaka T, Ichikawa I, Noda T, Ohno s.
  • Journal Title: PLoS ONE. 4(1)
  • Peer Reviewed
• [Journal Article] Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Prietal Cell Hyperplasia in a Murine Model of Celluar/Collapsing Focal Segmental Glomerulosclerosis. (2009)
  • Author(s): Suzuki T, Matsusaka T, Nakayama M, Asano T, Watanabe T, Ichikawa I, Nagata M.
  • Journal Title: Am J Pathol. 174(5)(in press)
  • Peer Reviewed
• [Journal Article] Fibrinogen That Appear in the Bowman's Space of Proteinuric Kidneys in vivo Activates Podocyte Toll-like Receptor 2 and 4 in vitro. (2009)
  • Author(s): Motojima M, Matsusaka T, Kon V, Ichikawa I.
  • Journal Title: Nephron Experimental (in press)
  • Peer Reviewed
• [Journal Article] Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. (2008)
  • Author(s): Motoyoshi Y, Matsusaka T, Saito A, Pastan I, Willnow TE, Mizutani S, Ichikawa I.
  • Journal Title: Kidney Int. 74(10) Pages: 1262-1269
  • NAID: 10026412041
  • Peer Reviewed
• [Journal Article] Bmp in podocytes is essential for normal glomerular capillary formation. (2008)
  • Author(s): Ueda H, Miyazaki Y, Matsusaka T, Utsunomiya Y, Kawamura T, Hosoya T, Ichikawa I.
  • Journal Title: J Am Soc Nephrol. 19(4) Pages: 685-694
  • Peer Reviewed
• [Journal Article] Bmp in Podocytes Is Essential for Normal Glomerular Capillary Formation. (2008)
  • Author(s): Ueda H, Miyazaki Y, Matsusaka T, Utsunomiya Y, Kawamura T, Hosoya T, Ichikawa I.
  • Journal Title: J Am Soc Nephrol 19(4) Pages: 685-694
  • Peer Reviewed
• [Journal Article] Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. (2008)
  • Author(s): Motoyoshi Y, Matsusaka T, Saito A, Pastan I, Willnow TE, Mizutani s, Ichikawa I.
  • Journal Title: Kidney Int. 74(10) Pages: 1262-1269
  • NAID: 10026412041
  • Peer Reviewed
• [Journal Article] Bmp in Podocytes Is Essential for Normal Glomerular Capillary Formation (2008)
  • Author(s): Ueda H, Miyazaki Y, Matsusaka T, Utsunomiya Y, Kawamura T, Hosoya T, Ichikawa I.
  • Journal Title: J Am Soc Nephrol (Epub Feb.)(in press)
  • Peer Reviewed
• [Journal Article] Angiotensin inhibition decreases progression of advanced atherosclerosis and stabilizes established atherosclerotic plaques. (2007)
  • Author(s): Suganuma E, Babaev VR, Motojima M, Zuo Y, Ayabe N, Fogo AB, Ichikawa I, Linton MF, Fazio S, Kon V.
  • Journal Title: J Am Soc Nephrol. 18(8) Pages: 2311-2319
  • Peer Reviewed
• [Journal Article] Effects of podocyte injury on glomerular development (2007)
  • Author(s): Ma J, Rossini M, Yang HC, Zuo Y, Fogo AB, Ichikawa I.
  • Journal Title: Pediatr Res 62(4) Pages: 417-421
  • Peer Reviewed
• [Journal Article] HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. (2006)
  • Author(s): Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, Jolicoeur P, Fogo AB, Ichikawa I.
  • Journal Title: J Am Soc Nephrol. 17(10) Pages: 2832-2843
  • Peer Reviewed
• [Journal Article] The renin-angiotensin system in the development of the congenital anomalies of the kidney and urinary tract. (2006)
  • Author(s): Niimura F, Kon V, Ichikawa I.
  • Journal Title: Curr Opin Pediatr. 18(2) Pages: 161-6
• [Journal Article] Inhibition of endogenous BMP in the glomerulus leads to mesangial matrix expansion. (2006)
  • Author(s): Miyazaki Y, Ueda H, Yokoo T, Utsunomiya Y, Kawamura T, Matsusaka T, Ichikawa I, Hosoya T.
  • Journal Title: Biochem Biophys Res Commun. 340(2) Pages: 681-688
  • Peer Reviewed
• [Journal Article] HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. (2006)
  • Author(s): Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, Jolicoeur P, Fogo AB, Ichikawa I.
  • Journal Title: J Am Soc Nephrol 17・10 Pages: 2832-2843
• [Journal Article] A role of BMP in the development of glomerular sclerosis. (2005)
  • Author(s): Ueda H, Miyazaki Y, Yokoo T, Utsunomiya Y, Kawamura T, Matsusaka T, Ichikawa I, Hosoya T.
  • Journal Title: Nephrology (Carlton). 10 Supple6
• [Journal Article] Podocyte damage damages podocytes : autonomous vicious cycle that drives local spread of glomerular sclerosis. (2005)
  • Author(s): Ichikawa I, Ma J, Motojima M, Matsusaka T.
  • Journal Title: Curr Opin Nephrol Hypertens. 14(3) Pages: 205-210
• [Journal Article] Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury. (2005)
  • Author(s): Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, Hashizume H, Wang QC, Pastan I, Fogo AB, Ichikawa I.
  • Journal Title: J Am Soc Nephrol. 16(4) Pages: 1013-1023
  • Peer Reviewed
• [Journal Article] Permanent genetic tagging of podocytes : fate of injured podocytes in a mouse model of glomerular sclerosis. (2005)
  • Author(s): Asano T, Niimura F, Pastan I, Fogo AB, Ichikawa I, Matsusaka T.
  • Journal Title: J Am Soc Nephrol. 16(8) Pages: 2257-2262
  • Peer Reviewed
• [Journal Article] Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. (2005)
  • Author(s): Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, Matsusaka T.
  • Journal Title: Kidney Int. 68(3) Pages: 1048-1060
  • Peer Reviewed
• [Journal Article] Interruption of Glomerular Filtration Interrupts the Pathogenic Pathway from Podocyte Injury to Glomerular Sclerosis. (2004)
  • Author(s): Matsusaka T, Fogo A, Pastan I, Ichikawa I.
  • Journal Title: J Am Soc Nephrol 15
• [Journal Article] HIV-1 Genes vpr and nef Synergistically Cause Podocyte Injury. (2004)
  • Author(s): Zuo Y, Zhong J, Ma J, Fogo A, Ichikawa I, Matsusaka T.
  • Journal Title: J Am Soc Nephrol 15
• [Journal Article] Identity of the Origin of Proliferating Visceral Epithelial Cells. (2004)
  • Author(s): Asano T, Matsusaka T, Fogo A, Ichikawa I.
  • Journal Title: J Am Soc Nephrol 15
• [Journal Article] The Role of BMP4 in Glomerulogenesis and Nephrogenesis. (2004)
  • Author(s): Ueda H, Miyazaki Y, Asano T, Matsusaka T, Utsunomiya Y, Kawamura T, Hosoya T, Ichikawa I.
  • Journal Title: J Am Soc Nephrol 15
• [Journal Article] Genetic engineering of glomerular sclerosis in the mouse via control of onset and of severity of podocyte-specific injury.
  • Author(s): Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, Hashizume H, Wang Q C, Pastan I, Fogo A, Ichikawa I.
  • Journal Title: J Am Soc Nephrol (in press)
• [Presentation] Augmented Expression of Renal Angiotensinogen and Intrarenal Vascular Hypertrophy in Hypotensive Mice with Liver-Specific Inactivation of Angiotensinogen. (2008)
  • Author(s): Niimura F, Matsusaka T, Asano T, Ichikawa I, Nishiyama A.
  • Organizer: American Society of Nephrology Renal Week 2008 Annual Meeting
  • Place of Presentation: Philadelphia.
• [Presentation] Nephrin Gene Expression in Podocytes Is Regulated by Histone Acetylation. (2008)
  • Author(s): Motojima M, Matsusaka T, Kon V, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2008 Annual Meeting.
  • Place of Presentation: Philadelphia.
• [Presentation] Angiotensin II Receptor (ATI) Antagonist Protects Podocytes through Mechanism(s) Independent of AT1 on Podocytes. (2008)
  • Author(s): Matsusaka T, Niimura F, Asano T, Fogo A, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2008 Annual Meeting.
  • Place of Presentation: Philadelphia.
• [Presentation] p21欠損実験腎炎マウスにおける上皮増殖病変ポドサイトタグ付け遺伝子改変マウスによる解析~壁側上皮由来の増殖. (2008)
  • Author(s): 鈴木大成、松阪泰二、浅野貴子、市川家國、長田道夫.
  • Organizer: 第51回日本腎臓学会学術総会.
  • Place of Presentation: 福岡.
• [Presentation] ポドサイトの修復と再生の可能性を求めて (2008)
  • Author(s): 松阪泰二、市川家國.
  • Organizer: 第51回日本腎臓学会学術総会.
  • Place of Presentation: 福岡
• [Presentation] p21欠損実験腎炎マウスにおける上皮増殖病変ポドサイトタグ付け遺伝子改変マウスによる解析〜壁側上皮由来の増殖 (2008)
  • Author(s): 鈴木大成, 松阪泰二, 浅野貴子, 市川家國, 長田道夫
  • Organizer: 第51回日本腎臓学会学術総会
  • Place of Presentation: 福岡県福岡市
• [Presentation] Augmented Expression of Renal Angiotensinogen and Intrarenal Vascular Hypertrophy in Hypotensive Mice with Liver-Specific Inactivation of Angiotensinogen. (2008)
  • Author(s): Niimura F, Matsusaka T, Asano T, Ichikawa I, Nishiyama A
  • Organizer: ASN Annual Meeting2008
  • Place of Presentation: 米国・フィラデルフィア
• [Presentation] Nephrin Gene Expression in Podocytes Is Regulated by Histone Acetylation. (2008)
  • Author(s): Motojima M, Matsusaka T, Kon V, Ichikawa l
  • Organizer: ASN Annual Meeting2008
  • Place of Presentation: 米国・フィラデルフィア
• [Presentation] Podocyte-Derived VEGF Serves as Their Own Protective and Survival Factor In Vitro. (2008)
  • Author(s): Ma J, Yang H, Matsusaka T, Zuo Y, Fogo A, Ichikawa l
  • Organizer: ASN Annual Meeting2008
  • Place of Presentation: 米国・フィラデルフィア
• [Presentation] Angiotensin II Receptor (ATI) Antagonist Protects Podocytes through Mechanism (s) Independent of AT1 on Podocytes (2008)
  • Author(s): Matsusaka T, Niimura F, Asano T, Fogo A, Ichikawa l
  • Organizer: ASN Annual Meeting2008
  • Place of Presentation: 米国・フィラデルフィア
• [Presentation] Megalin Mediates Tubule Injury Induced by Proteinuria. (2007)
  • Author(s): Motoyoshi Y, Matsusaka T, Saito A, Willnow TE, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2007 Annual Meeting
  • Place of Presentation: San Francisco.
• [Presentation] Nphs1-Cre/ROSA26-loxP Genetic Podocyte Tagging Revealed Parietal Cell Proliferation in p21 Deficient Mice with Experimental Glomerulonephritis. (2007)
  • Author(s): Suzuki S, Matsusaka T, Asano T, Ichikawa I, Nagata M.
  • Organizer: American Society of Nephrology Renal Week 2007 Annual Meeting.
  • Place of Presentation: San Francisco.
• [Presentation] Identification of Activators of Nephrin Gene Promoter. (2007)
  • Author(s): Motojima M, Matsusaka T, Kon V, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2007 Annual Meeting.
  • Place of Presentation: San Francisco.
• [Presentation] Megalin Mediates Tubular Injury Secondary to Glomerular Diseases. (2007)
  • Author(s): Motoyoshi Y, Matsusaka T, Ichikawa I.
  • Organizer: 14th Congress of the International Pediatric Nephrology Association.
  • Place of Presentation: Budapest
• [Presentation] 慢性腎臓病の非免疫学的進行機序に関する研究の流れと未来展望. (2007)
  • Author(s): 市川家國
  • Organizer: 第50回日本腎臓学会学術総会.
  • Place of Presentation: 浜松.
• [Presentation] 糸球体傷害に続発する尿細管傷害にはmegalinによる蛋白質再吸収が関与する (2007)
  • Author(s): 元吉八重子、松阪泰二、市川家國.
  • Organizer: 第50回日本腎臓学会学術総会
  • Place of Presentation: 浜松.
• [Presentation] 正常なポドサイトの数を増加させる事が可能である. (2007)
  • Author(s): 松阪泰二、市川家國
  • Organizer: 第50回日本腎臓学会学術総会.
  • Place of Presentation: 浜松.
• [Presentation] 慢性腎臓病の非免疫学的進行機序に関する研究の流れと未来展望 (2007)
  • Author(s): 市川 家國
  • Organizer: 第50回日本腎臓学会学術総会
  • Place of Presentation: 静岡県浜松市
• [Presentation] 糸球体傷害に続発する尿細管傷害にはmeaglinによる蛋白質再吸収が関与する (2007)
  • Author(s): 元吉 八重子、松阪 泰二、市川 家國
  • Organizer: 第50回日本腎臓学会学術総会
  • Place of Presentation: 静岡県浜松市
• [Presentation] Megalin Mediates Tubular Injury Secondary to Glomerular Diseases. (2007)
  • Author(s): Motoyoshi Y, Matsusaka T, Ichikawa I.
  • Organizer: 14th Congress of the International Pediatric Nephrology Association
  • Place of Presentation: ハンガリー・ブダペスト
• [Presentation] Megalin Mediates Tubule Injury Induced by Proteinuria (2007)
  • Author(s): Motoyosh i Y, Matsusaka T, Saito A, Willnow TE, Ichikawa I.
  • Organizer: ASN Annual Meeting 2007
  • Place of Presentation: 米国・サンフランシスコ
• [Presentation] Inducible Podocyte-Specific Overexpression of VEGF in Mice (2007)
  • Author(s): Ma J, Matsusaka T, Fogo AB, Ichikawa I
  • Organizer: ASN Annual Meeting 2007
  • Place of Presentation: 米国・サンフランシスコ
• [Presentation] Nphs1-Cre/ROSA26-loxP Genetic Podocyte Tagging Revealed Parietal Cell Proliferation in p21 Deficient Mice with Experimental Glomerulonephritis. (2007)
  • Author(s): Suzuki S, Matsusaka T, Asano T, Ichikawa I, Nagata M
  • Organizer: ASN Annual Meeting 2007
  • Place of Presentation: 米国・サンフランシスコ
• [Presentation] Identification of Activators of Nephrin Gene Promoter. (2007)
  • Author(s): Motojima M, Matsusaka T, Kon V, Ichikawa I
  • Organizer: ASN Annual Meeting 2007
  • Place of Presentation: 米国・サンフランシスコ
• [Presentation] Experimental attempt to increase podocyte number in vivo. (2006)
  • Author(s): Matsusaka T, Ichikawa I, Kopp J.
  • Organizer: American Society of Nephrology Renal Week 2006 Annual Meeting.
  • Place of Presentation: San Diego.
• [Presentation] Toll-like receptors in podocytes modulate response to injury. (2006)
  • Author(s): Motojima M, Matsusaka T, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2006 Annual Meeting.
  • Place of Presentation: San Diego.
• [Presentation] ポドサイトにおけるアンジオテンシンの役割 (2006)
  • Author(s): 浅野貴子、市川家國、新村文男、松阪泰二.
  • Organizer: 第41回日本小児腎臓病学会学術集会
  • Place of Presentation: 名古屋.
• [Presentation] BMP4の糸球体血管係蹄発生に対する調節機構. (2006)
  • Author(s): 上田裕之、宮崎陽一、松阪泰二、宇都宮保典、川村哲也、細谷龍男、市川家國.
  • Organizer: 第49回日本腎臓学会学術総会.
  • Place of Presentation: 東京
• [Presentation] ポドサイト再生の試み. (2006)
  • Author(s): 松阪泰二、市川家國.
  • Organizer: 第49 回日本腎臓学会学術総会
  • Place of Presentation: 東京
• [Presentation] Dual Effect of an α-Actinin-4 Gene Mutation on Podocyte Injury. (2005)
  • Author(s): Matsusaka T, Fogo A, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2005 Annual Meeting.
  • Place of Presentation: Philadelphia
• [Presentation] 糸球体病変が進行性に転じる際の上皮障害の役割. (2005)
  • Author(s): 市川家國.
  • Organizer: 第35 回日本腎臓学会東部学術集会.
  • Place of Presentation: 新潟.
• [Presentation] Interruption of Glomerular Filtration Interrupts the Pathogenic Pathway from Podocyte Injury to Glomerular Sclerosis. (2004)
  • Author(s): Matsusaka T, Fogo A, Pastan I, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2004 Annual Meeting.
  • Place of Presentation: Saint Louis.
• [Presentation] Identity of the Origin of Proliferating Visceral Epithelial Cells (2004)
  • Author(s): Asano T, Matsusaka T, Fogo A, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2004 Annual Meeting
  • Place of Presentation: Saint Louis.
• [Presentation] The Role of BMP4 in Glomerulogenesis and Nephrogenesis (2004)
  • Author(s): Ueda H, Miyazaki Y, Asano T, Matsusaka T, Utsunomiya Y, Kawamura T, Hosoya T, Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2004 Annual Meeting.
  • Place of Presentation: Saint Louis
• [Presentation] Analysis of Podocyte Injury Using Genetically Altered Mice (2004)
  • Author(s): Ichikawa I.
  • Organizer: American Society of Nephrology Renal Week 2004 Annual Meeting
  • Place of Presentation: Saint Louis.
• [Presentation] HIV-1 genes vpr and nef synergistically cause podocyte injury. (2004)
  • Author(s): Zuo Y, Zhong J, Ma J, Fogo AB, Ichikawa I, Matsusaka T.
  • Organizer: American Society of Nephrology Renal Week 2004 Annual Meeting
  • Place of Presentation: Saint Louis.
• [Presentation] Podocyte傷害と腎硬化 (2004)
  • Author(s): 松阪泰二、市川家國
  • Organizer: 第47回日本腎臓学会学術総会.
  • Place of Presentation: 宇都宮.
• [Presentation] 傷害を受けたpodocyteの運命の追跡 (2004)
  • Author(s): 浅野貴子、松阪泰二、新村文男、市川家國.
  • Organizer: 第47回日本腎臓学会学術総会
  • Place of Presentation: 宇都宮.
• [Presentation] BMP4による糸球体形態形成の調節機構 (2004)
  • Author(s): 上田裕之、宮崎陽一、浅野貴子、松阪泰二、宇都宮保典、川村哲也、細谷龍男、市川家國
  • Organizer: 第47回日本腎臓学会学術総会
  • Place of Presentation: 宇都宮