Motoko Yanagita

Research Overview

More than 320,000 patients with renal failure are undergoing hemodialysis in Japan. We are studying the regenerative ability of the kidney, which can be linked to the treatment of kidney disease. We have identified the cell populations responsible for kidney injury and repair, and have revealed the intercellular crosstalk which controls the development and progression of kidney disease. Fibrosis and renal anemia are the hallmarks of advanced kidney diseases. Previously we have found that these two features are caused by the fibroblasts-to-myofibroblasts transdifferentiation in the kidney. In addition, we have shown that the transdifferentiation of fibroblasts is induced by renal tubular damage, and that fibroblasts acquire the ability to produce retinoic acids during the transdifferentiation, which promotes tubular repair. Furthermore, we have shown that renal tubule has self-repairing ability, although the ability is not sufficient if the damage is severe. Elderly people have incomplete renal repair capacity, but the reason of incomplete repair was not clarified. We have shown that tertiary lymphoid tissues (TLTs) are formed in aged injured kidneys, and sustained inflammation due to TLT formation delays kidney regeneration. Interestingly, fibroblasts in the kidney acquire distinct phenotypes which promotes TLT formation in aged kidneys. In this project, we will extend our current understanding of the mechanisms of kidney injury with monkey models and human tissues.

Figure 1: Possible mechanism of kidney disease progression

Figure 2: Resident fibroblasts diversify into heterogeneous fibroblasts and orchestrate TLT formation

Publications

Shinya Yamamoto, Masamichi Yamamoto, Jin Nakamura, Akiko Mii, Shigenori Yamamoto, Masahiro Takahashi, Keiichi Kaneko, Eiichiro Uchino, Yuki Sato, Shingo Fukuma, Hiromi Imamura, Michiyuki Matsuda, Motoko Yanagita. “Spatiotemporal ATP dynamics during acute kidney injury predicts renal prognosis”. Journal of the American Society of Nephrology　2020 Dec;31(12):2855-2869. doi: 10.1681/ASN.2020050580. Epub 2020 Oct 12.

Yuki Sato, Peter Boor, Shingo Fukuma, Barbara M. Klinkhammer, Hironori Haga, Osamu Ogawa, Jürgen Floege and Motoko Yanagita. “Developmental stages of tertiary lymphoid tissue reflect local injury and inflammation in mouse and human kidneys”. Kidney Int. 2020 Aug;98(2):448-463. doi: 10.1016/j.kint.2020.02.023. Epub 2020 May 28.PMID: 32473779

Eiichiro Uchino , Kanata Suzuki , Noriaki Sato , Ryosuke Kojima , Yoshinori Tamada , Shusuke Hiragi , Hideki Yokoi , Nobuhiro Yugami , Sachiko Minamiguchi, Hironori Haga , Motoko Yanagita, Yasushi Okuno. “Classification of glomerular pathological findings using deep learning and nephrologist-AI collective intelligence approach”. Int J Med Inform. 2020 Jul 11;141:104231. doi: 10.1016/j.ijmedinf.2020.104231. Online ahead of print.PMID: 32682317

Zhengtao Qin, Carl K. Hoh, Emilia S. Olson, Amin Haghighat Jahromi, David J. Hall, Christopher V. Barback, Young-Hyun You, Motoko Yanagita, Kumar Sharma, and David R. Vera.“Molecular imaging of the glomerulus via mesangial cell uptake of radiolabeled tilmanocept”. J Nucl Med 2019 Feb 22 pii:jnumed.118.223727. doi: 10.2967/jnumed. 118.223727.[Epub ahedad of print] PMID:30796169

Jin Nakamura, Yuki Sato, Yuichiro Kitai, Shuichi Wajima, Shinya Yamamoto, Akiko Oguchi,Ryo Yamada, Keiichi Kaneko, Makiko Kondo, Eiichiro Uchino, Junichi Tsuchida, Keita Hirano,Kumar Sharma, Kenji Kohno, Motoko Yanagita. “M0yofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury”. Kidney Int. 2019 Mar;95(3):526-539. doi: 10.1016/j.kint.2018.10.017. Epub 2019 Jan 17. PMID:30661714

Taku Iguchi, Koji Takaori, Akiko Mii, Yuki Sato, Yasunori Suzuki, Hajime Yoshifuji, Hiroshi Seno, Osamu Ogawa, Koichi Omori, Kazuhisa Bessho, Satoru Kondo, Tomokazu Yoshizaki, Hitoshi Nakashima, Takao Saito, Tsuneyo Mimori, Hironori Haga, Mitsuhiro Kawano, Motoko Yanagita. “Glucocorticoid receptor expression in resident and hematopoietic cells in IgG4-related disease”. Mod Pathol. 2018 Jun;31(6):890-899. doi: 10.1038/s41379-018-0036-4. Epub 2018 Feb 12.

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. “Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney”. JCI Insight.2016 Jul 21; 1(11):e87680. DOI:10.1172/jci.insight.87680

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. “Severity and frequency of proximal tubule injury determines renal prognosis”. J Am Soc Nephrol. 2016 Aug;27(8):2393-406. doi: 10.1681/ASN.2015060647. Epub 2015 Dec 23.

Nariaki Asada, Masayuki Takase, Jin Nakamura, Akiko Oguchi, Misako Asada, Norio Suzuki, Ken-ichi Yamamura, Narihito Nagoshi, Shinsuke Shibata, Tata Nageswara Rao, Hans Joerg Fehling, Atsushi Fukatsu, Naoko Minegishi, Toru Kita, Takeshi Kimura, Hideyuki Okano, Masayuki Yamamoto, and Motoko Yanagita. “Dysfunction of fibroblasts of extra-renal origin underlies renal fibrosis and renal anemia in mice”. J Clin Invest. 2011 Oct;121(10):3981-90. doi: 10.1172/JCI57301. Epub 2011 Sep 12.

Mari Tanaka, Misako Asada, Atsuko Y Higashi, Jin Nakamura, Akiko Oguchi, Mayumi Tomita, Sachiko Yamada, Nariaki Asada, Masayuki Takase, Tomohiko Okuda, Hiroshi Kawachi, Aris N. Economides, Elizabeth Robertson, Satoru Takahashi, Takeshi Sakurai, Roel Goldschmeding, Eri Muso, Atsushi Fukatsu, Toru Kita, and Motoko Yanagita. “Loss of the BMP antagonist, USAG-1 ameliorates disease in a mouse model of progressive hereditary kidney disease Alport syndrome”. J Clin Invest. 2010 Mar;120(3):768-77. doi: 10.1172/JCI39569. Epub 2010 Feb 8.