DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

Ran Nakamichi; Akihito Hishikawa; Shunsuke Chikuma; Akihito Yoshimura; Takashi Sasaki; Akinori Hashiguchi; Takaya Abe; Tomoko Tokuhara; Norifumi Yoshimoto; Erina Sugita Nishimura; Eriko Yoshida Hama; Tatsuhiko Azegami; Takashin Nakayama; Kaori Hayashi; Hiroshi Itoh

doi:10.1016/j.celrep.2023.112302

DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

Ran Nakamichi, Akihito Hishikawa, Shunsuke Chikuma, Akihito Yoshimura, Takashi Sasaki, Akinori Hashiguchi, Takaya Abe, Tomoko Tokuhara, Norifumi Yoshimoto, Erina Sugita Nishimura, Eriko Yoshida Hama, Tatsuhiko Azegami, Takashin Nakayama, Kaori Hayashi, Hiroshi Itoh

Research Institute for Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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 CD44^high 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.

Original language	English
Article number	112302
Journal	Cell Reports
Volume	42
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2023.112302
Publication status	Published - 25 Apr 2023

Keywords

chronic kidney disease
CP: Immunology
CP: Molecular biology
DNA damage
DNA methylation
podocyte

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10.1016/j.celrep.2023.112302

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Nakamichi, R., Hishikawa, A., Chikuma, S., Yoshimura, A., Sasaki, T., Hashiguchi, A., Abe, T., Tokuhara, T., Yoshimoto, N., Nishimura, E. S., Hama, E. Y., Azegami, T., Nakayama, T., Hayashi, K., & Itoh, H. (2023). DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation. Cell Reports, 42(4), Article 112302. https://doi.org/10.1016/j.celrep.2023.112302

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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 = "chronic kidney disease, CP: Immunology, CP: Molecular biology, DNA damage, DNA methylation, 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",

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doi = "10.1016/j.celrep.2023.112302",

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Nakamichi, R, Hishikawa, A, Chikuma, S, Yoshimura, A, Sasaki, T, Hashiguchi, A, Abe, T, Tokuhara, T, Yoshimoto, N, Nishimura, ES, Hama, EY, Azegami, T, Nakayama, T, Hayashi, K & Itoh, H 2023, 'DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation', Cell Reports, vol. 42, no. 4, 112302. https://doi.org/10.1016/j.celrep.2023.112302

TY - JOUR

T1 - DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

AU - Nakamichi, Ran

AU - Hishikawa, Akihito

AU - Chikuma, Shunsuke

AU - Yoshimura, Akihito

AU - Sasaki, Takashi

AU - Hashiguchi, Akinori

AU - Abe, Takaya

AU - Tokuhara, Tomoko

AU - Yoshimoto, Norifumi

AU - Nishimura, Erina Sugita

AU - Hama, Eriko Yoshida

AU - Azegami, Tatsuhiko

AU - Nakayama, Takashin

AU - Hayashi, Kaori

AU - Itoh, Hiroshi

PY - 2023/4/25

Y1 - 2023/4/25

N2 - 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.

AB - 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.

KW - chronic kidney disease

KW - CP: Immunology

KW - CP: Molecular biology

KW - DNA damage

KW - DNA methylation

KW - podocyte

UR - https://www.scopus.com/pages/publications/85151474737

U2 - 10.1016/j.celrep.2023.112302

DO - 10.1016/j.celrep.2023.112302

M3 - Article

C2 - 36989112

AN - SCOPUS:85151474737

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 112302

ER -

DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

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