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.
Nakamura, J., Sato, Y., Kitai, Y., Wajima, S., Yamamoto, S., Oguchi, A., Yamada, R., Kaneko, K., Kondo, M., Uchino, E., Tsuchida, J., Hirano, K., Sharma, K., Kohno, K., Yanagita, M. (2019) Myofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury.Kidney Int.in press.
Sato, Y., Mii, A., Hamazaki, Y., Fujita, H., Nakata, H., Masuda, K., Nishiyama, S., Shibuya, S., Haga, H., Ogawa, O., Shimizu, A., Narumiya, S., Kaisho, T., Arita, M., Yanagisawa, M., Miyasaka, M., Sharma, K., Minato, N., Kawamoto, H., Yanagita, M. (2016) Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney.JCI Insight.1, e87680.
Takaori, K., Nakamura, J., Yamamoto, S., Nakata, H., Sato, Y., Takase, M., Nameta, M., Yamamoto, T., Economides, AN., Kohno, K., Haga, H., Sharma, K., Yanagita, M. (2016) Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis.J Am Soc Nephrol.27(8), 2393-406
Asada, N., Takase, M., Nakamura, J., Oguchi, A., Asada, M., Suzuki, N., Yamamura, K., Nagoshi, N., Shibata, S., Rao, TN., Fehling, HJ., Fukatsu, A., Minegishi, N., Kita, T., Kimura, T., Okano, H., Yamamoto, M., Yanagita, M. (2011) Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.J Clin Invest.121(10), 3981-90.
Tanaka, M., Asada, M., Higashi, AY., Nakamura, J., Oguchi, A., Tomita, M., Yamada, S., Asada, N., Takase, M., Okuda, T., Kawachi, H., Economides, AN., Robertson, E., Takahashi, S., Sakurai, T., Goldschmeding, R., Muso, E., Fukatsu, A., Kita, T., Yanagita, M. (2010) Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.J Clin Invest.120(3), 768-77.