DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation
Summary: 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,...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-04-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723003133 |
| _version_ | 1797856395864834048 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Ran Nakamichi |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-09T20:39:42Z |
| format | Article |
| id | doaj.art-162feb0aa04c4145b84d2e23b1f9dad3 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T20:39:42Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-162feb0aa04c4145b84d2e23b1f9dad32023-03-30T04:26:24ZengElsevierCell Reports2211-12472023-04-01424112302DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylationRan Nakamichi0Akihito Hishikawa1Shunsuke Chikuma2Akihito Yoshimura3Takashi Sasaki4Akinori Hashiguchi5Takaya Abe6Tomoko Tokuhara7Norifumi Yoshimoto8Erina Sugita Nishimura9Eriko Yoshida Hama10Tatsuhiko Azegami11Takashin Nakayama12Kaori Hayashi13Hiroshi Itoh14Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDepartment of Immunology, Keio University School of Medicine, Tokyo 160-8582, JapanDepartment of Immunology, Keio University School of Medicine, Tokyo 160-8582, JapanCenter for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-8582, JapanDepartment of Pathology, Keio University School of Medicine, Tokyo 160-8582, JapanLaboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, JapanLaboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; Corresponding authorDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, JapanSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723003133CP: ImmunologyCP: Molecular biology |
| spellingShingle | 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 DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation Cell Reports CP: Immunology CP: Molecular biology |
| title | DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation |
| title_full | DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation |
| title_fullStr | DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation |
| title_full_unstemmed | DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation |
| title_short | DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation |
| title_sort | dna damaged podocyte cd8 t cell crosstalk exacerbates kidney injury by altering dna methylation |
| topic | CP: Immunology CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723003133 |
| work_keys_str_mv | AT rannakamichi dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT akihitohishikawa dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT shunsukechikuma dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT akihitoyoshimura dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT takashisasaki dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT akinorihashiguchi dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT takayaabe dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT tomokotokuhara dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT norifumiyoshimoto dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT erinasugitanishimura dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT erikoyoshidahama dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT tatsuhikoazegami dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT takashinnakayama dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT kaorihayashi dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation AT hiroshiitoh dnadamagedpodocytecd8tcellcrosstalkexacerbateskidneyinjurybyalteringdnamethylation |