@article{56b495e940c545cca8cb6b985b590ab7,
title = "DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation",
abstract = "Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.",
keywords = "CP: Immunology, CP: Molecular biology, DNA damage, DNA methylation, chronic kidney disease, podocyte",
author = "Ran Nakamichi and Akihito Hishikawa and Shunsuke Chikuma and Akihito Yoshimura and Takashi Sasaki and Akinori Hashiguchi and Takaya Abe and Tomoko Tokuhara and Norifumi Yoshimoto and Nishimura, {Erina Sugita} and Hama, {Eriko Yoshida} and Tatsuhiko Azegami and Takashin Nakayama and Kaori Hayashi and Hiroshi Itoh",
note = "Funding Information: We acknowledge Dr. Mari Fujiwara (Core Facility, Collaborative Research Resources, Keio University School of Medicine) for technical assistance with flow-cytometry experiments, Dr. Atsushi Anzai and Dr. Seien Ko (Division of Cardiology, Keio University School of Medicine) for assistance with BM transplantation experiments, and Dr. Motoshi Hayano (Department of Psychiatry, Keio University) for a helpful discussion about pod I-PpoI mice. This study was supported by the JST FOREST Program (grant number JPMJFR210V, Japan), grants for scientific research (22H03091, 20H00535, 19K08688, and 20K17291) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Keio University research grants for life science and medicine, the Naito Memorial Foundation, the Takeda Science Foundation, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Tokyo, Japan. R.N. performed most of the experiments, analyzed the data, and wrote the manuscript. A. Hishikawa, T. Abe, and T.T. generated the pod I-PpoI mice, and A. Hishikawa wrote the manuscript. S.C. and A.Y. contributed to the immunology analysis. T.S. contributed to the analysis of the RNA-seq and scRNA-seq data. A. Hashiguchi contributed to the pathological analysis of human biopsies. N.Y. E.S.N. E.Y.H. T. Azegami, and T.N. contributed to the drafting and revision of the manuscript. K.H. conceived and designed the research studies, performed experiments, analyzed and interpreted the data, and wrote the manuscript. H.I. supervised the entire project and edited the manuscript. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We acknowledge Dr. Mari Fujiwara (Core Facility, Collaborative Research Resources, Keio University School of Medicine) for technical assistance with flow-cytometry experiments, Dr. Atsushi Anzai and Dr. Seien Ko (Division of Cardiology, Keio University School of Medicine) for assistance with BM transplantation experiments, and Dr. Motoshi Hayano (Department of Psychiatry, Keio University) for a helpful discussion about pod I-PpoI mice. This study was supported by the JST FOREST Program (grant number JPMJFR210V, Japan), grants for scientific research ( 22H03091 , 20H00535 , 19K08688 , and 20K17291 ) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Keio University research grants for life science and medicine, the Naito Memorial Foundation , the Takeda Science Foundation , and the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Tokyo, Japan. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = apr,
day = "25",
doi = "10.1016/j.celrep.2023.112302",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}