Elucidating the mechanisms of kidney fibrosis and regeneration

• Project/Area Number: 26293202
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: Yanagita Motoko 京都大学, 医学(系)研究科(研究院), 教授 (70378769)
• Co-Investigator(Kenkyū-buntansha): 河本 宏 京都大学, 再生医科学研究所, 教授 (00343228)
• Co-Investigator(Renkei-kenkyūsha): OKAMOTO Hitoshi 京都大学, 薬学研究科, 教授 (60158813)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 線維化 / 再生 / 炎症 / 老化 / 内科 / 再生医学 / 循環器 / 急性腎障害 / 慢性腎臓病 / 腎性貧血

Outline of Final Research Achievements

We demonstrated that proximal tubule injury induces the transdifferentiation of fibroblasts to myofibroblasts, and that the transdifferentiation is reversible when the proximal tubule injury is mild.
We also demonstrated that fibroblasts in aged kidney acquire the ability to produce homeostatic chemokines after injury, attract lymphocytes and trigger the formation of tertiary lymphoid tissues (TLTs). TLT formation in aged kidneys causes prolonged inflammation and delayed regeneration, and is frequently observed in aged human kidneys.

Research Products

• [Int'l Joint Research] University of San Diego/Regeneron Pharmaceuticals, Inc.(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Journal Article] Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney (2016)
  • Author(s): Yuki Sato, Akiko Mii, Yoko Hamazaki, Harumi Fujita, Hirosuke Nakata, Kyoko Masuda, Shingo Nishiyama, Shinsuke Shibuya, Hironori Haga, Osamu Ogawa, Akira Shimizu, Shuh Narumiya, Tsuneyasu Kaisho, Makoto Arita, Masashi Yanagisawa, Masayuki Miyasaka, Kumar Sharma, Nagahiro Minato, Hiroshi Kawamoto, Motoko Yanagita
  • Journal Title: JCI Insight Volume: 1(11)
  • NAID: 120005820865
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Insights into the Mechanisms of the Acute Kidney Injury-to-Chronic Kidney Disease Continuum (2016)
  • Author(s): Koji Takaori, Motoko Yanagita
  • Journal Title: Nephron Volume: 134(3) Pages: 172-176
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Severity and frequency of proximal tubule injury determines renal prognosis (2016)
  • Author(s): Koji Takaori, Jin Nakamura, Shinya Yamamoto, Hirosuke Nakata, Yuki Sato, Masayuki Takase, Masaaki Nameta, Tadashi Yamamoto, Aris N. Economides, Kenji Kohno, Hironori Haga, Kumar Sharma, Motoko Yanagita
  • Journal Title: J Am Soc Nephrol Volume: 27(8) Pages: 2393-406
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Time-dependent dysregulation of autophagy in the kidney: implications in aging and mitochondrial homeostasis (2016)
  • Author(s): Takeshi Yamamoto, Yoshitsugu Takabatake, Tomonori Kimura, Atsushi Takahashi, Tomoko Namba, Jun Matsuda, Jun-ya Kaimori, Isao Matsui, Harumi Kitamura, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Yoshitaka Isaka, Hiromi Rakugi
  • Journal Title: Autophagy Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ENOS deficiency causes podocyte injury with mitochondrial abnormality (2015)
  • Author(s): Shuko Ueda, Shota Ozawa, Kiyoshi Mori, Katsuhiko Asanuma, Motoko Yanagita, Shunya Uchida, Takahiko Nakagawa
  • Journal Title: Free Radical Biology & Medicine Volume: 87 Pages: 181-192
  • Peer Reviewed
• [Journal Article] MicroRNA-26a inhibits TGF-β-induced extracellular matrix expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy. (2015)
  • Author(s): Koga K, Yokoi H, Mori K, Kasahara K, Kuwabara T, Imamaki H, Ishii A, Mori KP, Kato Y, Ohno S, Toda N, Saleem MA, Sugawara A, Nakao K, Yanagita M, Mukoyama M.
  • Journal Title: Diabetologia Volume: 58 Pages: 2169-2180
  • DOI: 10.1007/s00125-015-3642-4
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Exploring the origin and limitations of kidney regeneration. (2015)
  • Author(s): Endo T, Nakamura J, Sato Y, Asada M, Yamada R, Takase M, Takaori K, Oguchi A, Iguchi T, Higashi AY, Ohbayashi T, Nakamura T, Muso E, Kimura T, Yanagita M.
  • Journal Title: Journal of Pathology Volume: 236(2) Pages: 251-263
  • DOI: 10.1002/path.4514
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Origin of myofibroblasts and cellular events triggering fibrosis. (2015)
  • Author(s): Matthias Mack, Motoko Yanagita
  • Journal Title: Kidney Int Volume: 87 Pages: 297-307
  • DOI: 10.1038/ki.2014.287
  • Peer Reviewed
• [Presentation] "Lessons from Animal Models of AKI to CKD Transition" (2016)
  • Author(s): Motoko Yanagita
  • Organizer: American Society of Nephrology
  • Place of Presentation: Chicago, U.S.A.
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] "Age-Dependent Tertiary Lymphoid Tissue Formation In The Kidney As A Novel Therapeutic Target" (2016)
  • Author(s): Yuki Sato, Akiko Mii, Hirosuke Nakata, Shingo Nishiyama, Motoko Yanagita
  • Organizer: American Society of Nephrology
  • Place of Presentation: Chicago, U.S.A.
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] "Lineage Tracing Analysis Elucidating the Behaviors of Erythropoietin Producing Cells" (2016)
  • Author(s): Keiichi Kaneko, Misako Asada, Motoko Yanagita
  • Organizer: American Society of Nephrology
  • Place of Presentation: Chicago, U.S.A.
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] 「老化と炎症」 (2016)
  • Author(s): 柳田 素子
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: 横浜、日本
  • Year and Date: 2016-06-18
• [Presentation] 「ESRD治療の今後」 (2016)
  • Author(s): 柳田 素子
  • Organizer: 第61回日本透析医学会学術集会・総会
  • Place of Presentation: 大阪、日本
  • Year and Date: 2016-06-09
  • Invited
• [Presentation] Severity, Frequency and Prevalence of Proximal Tubule Injury Determines Renal Prognosis (2015)
  • Author(s): Koji Takaori, Jin Nakamura, Tadashi Yamamoto, Kumar Sharma, Motoko Yanagita
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2015-11-03
• [Presentation] Establishment of a Novel Mouse Strain to Trace Erythropoietin Producing Cells at Desired Time Points (2015)
  • Author(s): Keiichi Kaneko, Motoko Yanagita
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2015-11-03
• [Presentation] 肥満と腎障害 (2015)
  • Author(s): 柳田素子
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] AKI to CKD Continuumにおける障害近位尿細管の役割 (2015)
  • Author(s): 高折光司、中村仁、山本伸也、柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05 – 2015-06-07
• [Presentation] レチノイドシグナルを介した尿細管上皮・線維芽細胞相互作用の解明 (2015)
  • Author(s): 中村仁、小口綾貴子、山田龍、柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05 – 2015-06-07
• [Presentation] AKIからCKD・末期腎不全への移行の分子基盤の解明 (2015)
  • Author(s): 柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05 – 2015-06-07
  • Invited
• [Presentation] AKIからCKDへの移行の分子基盤の解明 (2015)
  • Author(s): 柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-06-05
  • Invited
• [Presentation] AKI to CKD Continuumにおける障害近位尿細管の役割 (2015)
  • Author(s): 高折光司、中村仁、山本伸也、柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-06-05
• [Presentation] レチノイドシグナルを介した尿細管上皮ー線維芽細胞相互作用の解明 (2015)
  • Author(s): 中村仁、小口綾貴子、柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-06-05
• [Presentation] エリスロポエチン産生細胞の系譜追跡系の確立と線維化腎における動態の評価 (2015)
  • Author(s): 金子惠一、浅田三咲子、柳田素子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-06-05
• [Presentation] 腎臓病治療の将来：basic scienceからonconephrologyまで (2015)
  • Author(s): 柳田素子
  • Organizer: 日本麻酔科学会 第62回学術集会
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2015-05-28
  • Invited
• [Presentation] Selective proximal tubule injury causes interstitial fibrosis, distal tubule impairment and proteinuria (2014)
  • Author(s): Koji Takaori , Jin Nakamura, Tadashi Yamamoto, Motoko Yanagita
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: フィラデルフィア
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] Exploring the pathophysiological functions of resident fibroblasts in the kidney (2014)
  • Author(s): Jin Nakamura, Akiko Oguchi, Ryo Yamada, Motoko Yanagita
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: フィラデルフィア
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] Cellular events and factors modulating fibrosis (2014)
  • Author(s): 柳田素子
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-04 – 2014-07-06
  • Invited
• [Presentation] 慢性腎臓病における上皮-線維芽細胞相互作用の解明 (2014)
  • Author(s): 中村 仁、小口 綾貴子、山田 龍、土田 潤一、柳田 素子
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] 近位尿細管障害は線維化、遠位尿細管障害およびアルブミン尿を惹起する (2014)
  • Author(s): 高折 光司、中村 仁、山本 格、柳田 素子
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] 腎臓病治療の可能性を探る：basic scienceからonco-nephrologyまで (2014)
  • Author(s): 柳田素子
  • Organizer: 第59回日本透析医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2014-06-12 – 2014-06-15
  • Invited
• [Remarks] 京都大学医学研究科 腎臓内科学
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp
• [Remarks] 京都大学大学院医学研究科腎臓内科学
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp