The pathogenesis of progressive chronic renal disease and therapeutic strategies, based on the axis of macrophages and myofibroblasts

2013 Fiscal Year Final Research Report

• Project/Area Number: 22380173
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Clinical veterinary science
• Research Institution: Osaka Prefecture University
• Principal Investigator: YAMATE Jyoji 大阪府立大学, 生命環境科学研究科(系), 教授 (50150115)
• Co-Investigator(Kenkyū-buntansha): KUWAMURA Mitsuru 大阪府立大学, 生命環境科学研究科, 准教授 (20244668) ; TAKANAKA Shigeo 大阪府立大学, 生命環境科学研究科, 准教授 (10280067) ; AKIYOSHI Shigeyasu 大阪府立大学, 生命環境科学研究科, 准教授 (50420740) ; IZAWA Takeshi 大阪府立大学, 生命環境科学研究科, 助教 (20580369)
• Project Period (FY): 2010-04-01 – 2014-03-31
• Keywords: 腎線維化 / マクロファージ / 筋線維芽細胞 / 誘導因子 / MHCクラスII / EMT

Research Abstract

Fibrosis is developed after tissue injury. Regardless etiology,interstitial fibrosis occurs after renal injury, then leading to chronic kidney disease.The properties of macrophages and myofibroblasts, both which play central roles in fibrosis, were investigated using cisplatin-induced rat renal failure model. CD68 macrophages appeared at early stages, whereas at the advanced stages, MHC class II-expressing macrophages and lymphocytes appeared. Besides epithelial-mesenchymal transition (EMT), myofibroblasts may be derived from mesenchymal cells such as medullary interstitial cells and pericytes in lineage of stem cells. EMT phenomenon was seen exclusively in abnormally regenerating renal epithelia; the formation is inhibited by PGE2 but promoted by osteopontin. Characteristics of hepatic, pulomonary and cutaneous fibrosis were investigated as well. Clarifying the pathogenesis of fibrosis could lead to exploration of possible therapies.

Research Products

• [Journal Article] M1- and M2-macrophage polarization in thioacetamide (TAA)-induced rat liver lesions; a possible analysis for hepato-pathology (2014)
  • Author(s): Wijesundera, K.K., Izawa, T., Murakami, H., Tennakoon, A.H., Golbar, H.M., Kato-Ichikawa, C., Tanaka, M., Kuwamura, M., Yamate, J
  • Journal Title: Histol Histopathol Volume: 29 Pages: 497-511
  • Peer Reviewed
• [Journal Article] Characterization of glial fibrillary acidic protein (GFAP)-expressing hepatic stellate cells and myofibroblasts in thioacetamide (TAA)-induced rat liver injury (2013)
  • Author(s): Tennakoon, A.H., Izawa, T., Wijesundera, K.K., Golbar, H.M., Tanaka, M., Ichikawa, C., Kuwamura, M., Yamate, J.
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 1159-1171
  • DOI: 10.1016/j.etp.2013.05.008
  • Peer Reviewed
• [Journal Article] Expressions of Iba1 and galectin-3 (Gal-3) in thioacetamide (TAA)-induced acute rat liver lesions (2013)
  • Author(s): Wijesundera, K.K., Juniantito, V., Golbar, H.M., Fujisawa, K., Tanaka, M., Ichikawa, C., Izawa, T., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 799-808
  • DOI: 10.1016/j.etp.2012.11.006
  • Peer Reviewed
• [Journal Article] Thy-1 expression, a possible marker of early myofibroblast development, in renal tubulointerstitial fibrosis induced in rats by cisplatin (2013)
  • Author(s): Yuasa, T., Juniantito, V., Ichikawa, C., Yano, R., Izawa, T., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 651-659
  • DOI: 10.1016/j.etp.2012.07.005
  • Peer Reviewed
• [Journal Article] Immunophenotypical analysis of myofibroblasts and mesenchymal cells in the bleomycin-induced rat scleroderma, with particular reference to their origin (2013)
  • Author(s): Juniantito, V., Izawa, T., Yuasa, T., Ichikawa, C., Tanaka, M., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 567-577
  • DOI: 10.1016/j.etp.2012.05.002
  • Peer Reviewed
• [Journal Article] Immunohistochemical characterization of macrophages and myofibroblasts in fibrotic liver lesions due to fasciola infection in cattle (2013)
  • Author(s): Golbar, H.M., Izawa, T., Juniantito, V., Ichikawa, C., Tanaka, M., Kuwamura, M., Yamate, J.
  • Journal Title: J Vet Med Sci Volume: 75 Pages: 857-865
  • Peer Reviewed
• [Journal Article] Distribution of cells labelled by a novel somatic stem cell-recognizing antibody (A3) in pulmonary genesis and bleomycin induced pulmonary fibrosis in rats (2013)
  • Author(s): Hori, M., Juniantito, V., Izawa, T., Ichikawa, C., Tanaka, M., Tanaka, K., Takenaka, S., Kuwamura, M., Yamate, J
  • Journal Title: J Comp Pathol Volume: 148 Pages: 385-395
  • DOI: 10.1016/j.jcpa.2012.09.003
  • Peer Reviewed
• [Journal Article] Immunophenotypical characterization of macrophages in rat bleomycin-induced scleroderma (2013)
  • Author(s): Juniantito, V., Izawa, T., Yuasa, T., Ichikawa, C., Yano, R., Kuwamura, M., Yamate, J
  • Journal Title: Vet Pathol Volume: 50 Pages: 76-85
  • DOI: 10.1177/0300985812450718
  • Peer Reviewed
• [Journal Article] Differential renal glomerular changes induced by 5/6 nephrectomization between common marmoset monkeys (Callithrix jacchus) and rats (2013)
  • Author(s): Suzuki Y, Yamaguchi I, Onoda N, Saito T, Myojo K, Imaizumi M, Takada C, Kimoto N, Takaba K, Yamate J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 667-676
  • DOI: 10.1016/j.etp.2012.08.001
  • Peer Reviewed
• [Journal Article] 腎疾患モデルと腎線維化の病理発生 (2013)
  • Author(s): 山手丈至
  • Journal Title: 臨床と病理 Pages: 1387-1394
• [Journal Article] Immunophenotypical analyses of myofibroblasts in rat excisional wound healing : possible transdifferentiation of blood vessel pericytes and perifollicular dermal sheath cells into myofibroblasts (2012)
  • Author(s): Juniantito, V., Izawa, T., Yuasa, T., Ichikawa, C., Yamamoto, E., Kuwamura, M., Yamate, J
  • Journal Title: Histol Histopathol Volume: 27 Pages: 515-527
  • Peer Reviewed
• [Journal Article] Immunohistochemical analyses of the kinetics and distribution of macrophages, hepatic stellate cells and bile duct epithelia in the developing rat liver (2012)
  • Author(s): Golbar, H.M., Izawa, T., Murai, F., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 64 Pages: 1-8
  • DOI: 10.1016/j.etp.2010.05.011
  • Peer Reviewed
• [Journal Article] Immunohistochemical expressions of main PGE2 biosynthesis-related enzymes and PGE2 receptor in rat nephrogenesis (2011)
  • Author(s): Yamamoto, E., Izawa, T., Kuwamura, M., Yamate, J
  • Journal Title: J Toxicol Pathol Volume: 24 Pages: 257-261
  • DOI: 10.1293/tox.24.257
  • Peer Reviewed
• [Journal Article] Heterogeneity of macrophage populations and expression of galectin-3 in cutaneous wound healing in rats (2011)
  • Author(s): Juniantito, V., Izawa, T., Yamamoto, E., Murai, F., Kuwamura, M., Yamate, J
  • Journal Title: J Comp Pathol Volume: 145 Pages: 378-389
  • DOI: 10.1016/j.jcpa.2011.01.012
  • Peer Reviewed
• [Journal Article] Relationship of heat shock protein 25 with reactive macrophages in thioacetamide-induced rat liver injury (2011)
  • Author(s): Fujisawa, K., Miyoshi, T., Tonomura, Y., Izawa, T., Kuwamura, M., Torii, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 63 Pages: 599-605
  • DOI: 10.1016/j.etp.2010.04.014
  • Peer Reviewed
• [Journal Article] Immunohistochemical characterization of macrophages and myofibroblasts in alpha-Naphthylisothiocyanate (ANIT)-induced bile duct injury and subsequent fibrogenesis in rats (2011)
  • Author(s): Golbar, H.M., Izawa, T., Yano, R., Ichikawa, C., Sawamoto, O., Kuwamura, M., LaMarre, J., Yamate, J
  • Journal Title: Toxicol Pathol Volume: 39 Pages: 795-808
  • DOI: 10.1177/0192623311413790
  • Peer Reviewed
• [Journal Article] Thy-1 expressing mesenchymal cells in rat nephrogenesis in correlation with cells immunoreactive for alpha-smooth muscle actin and vimentin (2010)
  • Author(s): Yuasa, T., Izawa, T., Kuwamura, M., Yamate, J
  • Journal Title: J Toxicol Pathol Volume: 23 Pages: 1-10
  • DOI: 10.1293/tox.23.1
  • Peer Reviewed
• [Journal Article] The kinetics and distribution of different macrophage populations in the developing rat skin (2010)
  • Author(s): Juniantito, V., Izawa, T., Yamamoto, E., Kuwamura, M., Yamate, J
  • Journal Title: Histol Histopathol Volume: 25 Pages: 985-994
  • Peer Reviewed
• [Journal Article] Involvement of endogenous prostaglandin E2 in tubular epithelial regeneration through inhibition of apoptosis and epithelial-mesenchymal transition in cisplatin-induced rat renal lesions (2010)
  • Author(s): Yamamoto, E., Izawa, T., Juniantito, V., Kuwamura, M., Sugiura, K., Takeuchi, T., Yamate, J
  • Journal Title: Histol Histopathol Volume: 25 Pages: 995-1007
  • Peer Reviewed
• [Journal Article] Relationship of cell proliferating marker expressions with PGE2 receptors in regenerating rat renal tubules after cisplatin injection (2010)
  • Author(s): Yamamoto, E., Izawa, T., Juniantito, V., Kuwamura, M., Yamate, J
  • Journal Title: J Toxicol Pathol Volume: 23 Pages: 271-275
  • DOI: 10.1293/tox.23.271
  • Peer Reviewed
• [Presentation] 正常肝と肝硬変ラットにおける上皮-間葉転換の観点からの肝星細胞の特徴解析 (2014)
  • Author(s): Tennakoon A, 井澤武史, Wijesundera K, Golbar HM,田中美有, 桑村 充, 山手丈至
  • Organizer: 第30回日本毒性病理学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 20140130-31
• [Presentation] Participation of macrophage populations in GST-P-positive liver lesions induced in rats by repeated injections of thioacetamide (TAA) (2013)
  • Author(s): Wijesundera K, Izawa T, Katou-Ichikawa C, Tennakoon A, Murakami H, Golbar H, Kuwamura M, and Yamate J
  • Organizer: ACVP & ASVCP 2013 Concurrent Annual Meeting
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20131118-20
• [Presentation] Different macrophage populations in pseudolobules (PLs) with or without adipophilin expression in thioacetamide (TAA)-induced rat cirrhosis (2013)
  • Author(s): Wijesundera K, 井澤武史, Tennakoon A, 藤智彩, Golbar HM, 桑村充, 山手丈至
  • Organizer: 第156回日本獣医学会学術集会
  • Place of Presentation: 岐阜
  • Year and Date: 20130921-23
• [Presentation] シスプラチン誘発ラット腎線維化におけるマクロファージの機能特性の解析 (2013)
  • Author(s): 松山 聡, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第156回日本獣医学会学術集会
  • Place of Presentation: 岐阜
  • Year and Date: 20130921-23
• [Presentation] α-naphthylisothiocyanate(ANIT)により誘発したラットの急性と慢性胆管病変におけるマクロファージと筋線維芽細胞の特性比較 (2013)
  • Author(s): Golbar HM, 井澤武史, 市川智彩, 田中美有, 桑村 充, 山手丈至
  • Organizer: 第29回日本毒性病理学会学術集会
  • Place of Presentation: つくば
  • Year and Date: 20130121-0201
• [Presentation] シスプラチン誘発ラット腎障害モデルでの再生尿細管におけるβ-カテニンの発現 (2012)
  • Author(s): 寺田直美, 市川智彩, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第154回日本獣医学会学術集会
  • Place of Presentation: 盛岡
  • Year and Date: 20120914-16
• [Presentation] シスプラチン誘発ラット腎間質線維化におけるカルポニンの発現と筋線維芽細胞との関連 (2012)
  • Author(s): 湯浅隆弘, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第28回日本毒性病理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20120202-03
• [Presentation] シスプラチン誘発ラット急性腎障害モデルにおけるバイオマーカーの発現動態 (2012)
  • Author(s): 山本絵美, 増野功一, 藤澤可恵, 土屋紀子, 松嶋周一, 高須伸夫, 鳥井幹則, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第28回日本毒性病理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20120202-03
• [Presentation] M1/M2 macrophage polarization in thioacetamide (TAA)-induced acute rat liver lesions (2012)
  • Author(s): Wijesundera K,Golbar HM,市川智彩, 田中美有, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第28回日本毒性病理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20120202-03
• [Presentation] Mechanisms of cutaneous wound healing, based on functional properties of macrophages and myofibroblasts (2012)
  • Author(s): Yamate J
  • Organizer: 第153回日本獣医学会学術集会
  • Place of Presentation: スライドセミナー. 東京
  • Year and Date: 2012-03-29
  • Invited
• [Presentation] Immunohistochemical characterization of macrophages and myofibroblasts in biliary cirrhosis due to liver fluke (Fasciola spp) infestation in cattle (2011)
  • Author(s): Golbar HM, Juniantito V, Ichikawa C, Tanaka M, Izawa T, Kuwamura M, Yamate J
  • Organizer: The Joint Meeting of the 5th Conference and Congress of Asian Society of Veterinary Pathology (ASVP) 2011 and the 10th Scientific Symposium of Indonesia Society of Veterinary Pathology (ISVP) 2011
  • Place of Presentation: Bogor, Indonesia
  • Year and Date: 20111122-23
• [Presentation] Immunohistochemical detection of macrophages and myofibroblasts in rat model of bleomycin-induced scleroderma (2011)
  • Author(s): Juniantito V, Ichikawa C, Izawa T, Kuwamura M, Yamate J
  • Organizer: The Joint Meeting of the 5th Conference and Congress of Asian Society of Veterinary Pathology (ASVP) 2011 and the 10th Scientific Symposium of Indonesia Society of Veterinary Pathology (ISVP) 2011
  • Place of Presentation: Bogor, Indonesia
  • Year and Date: 20111122-23
• [Presentation] Expression of Iba1 and galectin-3 (Gal-3) in thioacetamide (TAA)-induced acute rat liver lesions (2011)
  • Author(s): Wijesundera K, Juniantito V,Golbar HM,藤澤可恵 ,田中美有, 市川智彩, 井澤武史 ,桑村 充, 山手丈至
  • Organizer: 第152回日本獣医学会学術集会
  • Place of Presentation: 堺
  • Year and Date: 20110919-21
• [Presentation] Nestin expression in α-naphthylisocyanate (ANIT)-induced acute bile duct injury lesions in rats (2011)
  • Author(s): Golbar HM,井澤武史, 市川智彩, 田中美有, 桑村 充, 山手丈至
  • Organizer: 第152回日本獣医学会学術集会
  • Place of Presentation: 堺
  • Year and Date: 20110919-21
• [Presentation] Immunophenotypical properties of macrophages and myofibroblasts in fasciola-infested cirrhotic cattle liver (2011)
  • Author(s): Golbar HM,井澤武史, 桑村 充, 山手丈至
  • Organizer: 第151回日本獣医学会学術集会
  • Place of Presentation: 府中
  • Year and Date: 20110330-31
• [Presentation] Involvement of macrophages and myofibroblasts in chronic ANIT-induced peribiliary fibrosis in rat model (2011)
  • Author(s): Golbar HM, 井澤武史, 矢野遼, 澤本修, 桑村 充, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110127-28
• [Presentation] 四塩化炭素誘発肝病変におけるHeat shock protein 25 とAdipophilin の発現動態 (2011)
  • Author(s): 藤澤可恵, 山本絵美, 増野功一, 土屋紀子,松 嶋周一, 高須伸夫, 井澤武史, 桑村 充, 鳥井幹則, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110127-28
• [Presentation] シスプラチン誘発ラット腎傷害における内因性PGE2 の影響 (2011)
  • Author(s): 山本絵美, 増野功一, 藤澤可恵, 土屋紀子, 松嶋周一, 高須伸夫, 鳥井幹則, 井澤武史, Juniantito V,桑村 充, 杉浦喜久弥, 竹内正吉, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110127-28
• [Presentation] ラット腎間質線維化におけるThy-1 免疫陽性細胞の動態 (2011)
  • Author(s): 湯浅隆弘, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110127-28
• [Presentation] Comparisons of properties of macrophages and myofibroblasts between two different cutaneous fibrosis rat models.Juniantito V (2011)
  • Author(s): 井澤武史, 矢野遼, 桑村 充, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110127-28
• [Book] 動物病理学総論 (2013)
  • Author(s): 山手丈至
  • Total Pages: 122-126
  • Publisher: 日本獣医学会編