Research Overview
Chronic kidney disease (CKD) affects over 10% of the global population, yet a definitive cure remains elusive. Therefore, we are investigating (1) kidney energy metabolism and (2) tertiary lymphoid structures (TLSs) with the goal of advancing kidney disease treatment towards a curable outcome.
(1) The kidney constantly utilizes ATP for substance reabsorption. To investigate the profiles of kidney energy metabolism and the association between energy metabolism and kidney injury, we utilize multiphoton microscopy alongside GO-ATeam2 mice, which express an ATP FRET biosensor. This approach allows us to visualize ATP dynamics and discern cell type–specific ATP dynamics after ischemia-reperfusion injury (IRI). Furthermore, we have observed that following IRI, inadequate ATP recovery in proximal tubules and podocytes is associated with interstitial fibrosis and albuminuria in the chronic phase, respectively. Our ATP visualization technology can elucidate metabolic alterations in pathological kidneys, facilitate nephrotoxic drugs screening.
(2) Older patients often experience suboptimal recovery following acute kidney injury, which frequently progresses to CKD and ultimately end-stage kidney disease. We have identified that TLS is a contributing factor to this maladaptive repair process, and kidney resident fibroblasts with distinct phenotypes and aging-associated T and B cells are crucial for TLS development. To elucidate the mechanism by which TLS induces kidney injury, we conducted single nucleus RNA-sequencing analysis and demonstrated that proinflammatory cytokines, such as TNFα and INFγ, are excessively produced by immune cells within TLSs. These cytokines induce proinflammatory characteristics in injured proximal tubules, which are preferentially localized around TLSs, thereby exacerbating tissue inflammation and fibrosis, and inhibiting normal repair. We also have shown that TLSs are associated with poor graft outcomes in transplanted kidneys and correlate with fibrosis severity in the liver of HCV hepatitis. Our future research will focus on elucidating TLS developmental mechanisms and their roles, with the goal of developing targeted therapies.
TLS develop in aged injured kidney, contributing to maladaptive repair. Differentiated fibroblasts and interactions between age-associated lymphocytes are crucial for TLS development.
Publications
Toriu, N., Sato, Y., Kamimura, H., Yoshikawa, T., Tanaka, M., Yamamoto, S., Fukuma, S., Hattori, M., Terai, S., & Yanagita, M. (2025). Aligning cellular and molecular components in age-dependent tertiary lymphoid tissues of kidney and liver. PLoS ONE, 20(2), e0311193. https://doi.org/10.1371/journal.pone.0311193
Kitai, Y., Toriu, N., Yoshikawa, T., Sahara, Y., Kinjo, S., Shimizu, Y., Sato, Y., Oguchi, A., Yamada, R., Kondo, M., Uchino, E., Taniguchi, K., Arai, H., Sasako, T., Haga, H., Fukuma, S., Kubota, N., Kadowaki, T., Takasato, M., Murakawa, Y., & Yanagita, M. (2025). Female sex hormones inversely regulate acute kidney disease susceptibility throughout life. Kidney International, 107(1), 68–83. https://doi.org/10.1016/j.kint.2024.08.034
Takahashi, M., Yamamoto, S., Yamamoto, S., Okubo, A., Nakagawa, Y., Kuwahara, K., Matsusaka, T., Fukuma, S., Yamamoto, M., Matsuda, M., & Yanagita, M. (2024). ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice. Nature Communications, 15(1), 9977. https://doi.org/10.1038/s41467-024-54222-0
Yamamoto, S., Yamamoto, S., Takahashi, M., Mii, A., Okubo, A., Toriu, N., Nakagawa, S., Abe, T., Fukuma, S., Imamura, H., Yamamoto, M., & Yanagita, M. (2024). Visualization of intracellular ATP dynamics in different nephron segments under pathophysiological conditions using the kidney slice culture system. Kidney International. Advance online publication. https://doi.org/10.1016/j.kint.2024.05.028
Oguchi, A., Suzuki, A., Komatsu, S., Yoshitomi, H., Bhagat, S., Son, R., Bonnal, R. J. P., Kojima, S., Koido, M., Takeuchi, K., ... Yanagita, M. (2024). An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases. Science, 385(6704), eadd8394. https://doi.org/10.1126/science.add8394
Yoshikawa, T., Oguchi, A., Toriu, N., Sato, Y., Kobayashi, T., Ogawa, O., Haga, H., Sakurai, S., Yamamoto, T., Murakawa, Y., & Yanagita, M. (2023). Tertiary lymphoid tissues are microenvironments with intensive interactions between immune cells and proinflammatory parenchymal cells in aged kidneys. Journal of the American Society of Nephrology, 34(10), 1687–1708. https://doi.org/10.1681/ASN.0000000000000202
Sato, Y., Oguchi, A., Fukushima, Y., Masuda, K., Toriu, N., Taniguchi, K., Yoshikawa, T., Cui, X., Kondo, M., Hosoi, T., ... Yanagita, M. (2022). CD153/CD30 signalling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. Journal of Clinical Investigation, 132(2), e146071. https://doi.org/10.1172/JCI146071
Lee, Y. H., Sato, Y., Saito, M., Fukuma, S., Saito, M., Yamamoto, S., Komatsuda, A., Fujiyama, N., Satoh, S., Lee, S.-H., ... Yanagita, M. (2022). Advanced tertiary lymphoid tissues in protocol biopsies are associated with progressive graft dysfunction in kidney transplant recipients. Journal of the American Society of Nephrology, 33(1), 186–200. https://doi.org/10.1681/ASN.2021050715
Kaneko, K., Sato, Y., Uchino, E., Toriu, N., Shigeta, M., Kiyonari, H., Endo, S., Fukuma, S., & Yanagita, M. (2022). Lineage tracing analysis defines erythropoietin-producing cells as a distinct subpopulation of resident fibroblasts with unique behaviors. Kidney International, 102(2), 280–292. https://doi.org/10.1016/j.kint.2022.04.026
Yamamoto, S., Yamamoto, M., Nakamura, J., Mii, A., Yamamoto, S., Takahashi, M., Kaneko, K., Uchino, E., Sato, Y., Fukuma, S., ... Yanagita, M. (2020). Spatiotemporal ATP dynamics during acute kidney injury predicts renal prognosis. Journal of the American Society of Nephrology, 31(12), 2855–2869. https://doi.org/10.1681/ASN.2020050580