DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages
Abstract DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfu...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59297-x |
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| author | Erina Sugita Nishimura Akihito Hishikawa Ran Nakamichi Riki Akashio Shunsuke Chikuma Akinori Hashiguchi Norifumi Yoshimoto Eriko Yoshida Hama Tomomi Maruki Wataru Itoh Shintaro Yamaguchi Jun Yoshino Hiroshi Itoh Kaori Hayashi |
| author_facet | Erina Sugita Nishimura Akihito Hishikawa Ran Nakamichi Riki Akashio Shunsuke Chikuma Akinori Hashiguchi Norifumi Yoshimoto Eriko Yoshida Hama Tomomi Maruki Wataru Itoh Shintaro Yamaguchi Jun Yoshino Hiroshi Itoh Kaori Hayashi |
| author_sort | Erina Sugita Nishimura |
| collection | DOAJ |
| description | Abstract DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6Chi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages. |
| format | Article |
| id | doaj-art-42fdef048d16492f93dedfb594d5b671 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-42fdef048d16492f93dedfb594d5b6712025-08-20T01:47:29ZengNature PortfolioNature Communications2041-17232025-04-0116112010.1038/s41467-025-59297-xDNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophagesErina Sugita Nishimura0Akihito Hishikawa1Ran Nakamichi2Riki Akashio3Shunsuke Chikuma4Akinori Hashiguchi5Norifumi Yoshimoto6Eriko Yoshida Hama7Tomomi Maruki8Wataru Itoh9Shintaro Yamaguchi10Jun Yoshino11Hiroshi Itoh12Kaori Hayashi13Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDepartment of Immunology, Keio University School of MedicineDepartment of Pathology, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineSchool of Medicine Medical Education Center, Keio UniversityDivision of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane UniversityCenter for Preventive Medicine, Keio University HospitalDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of MedicineAbstract DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6Chi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.https://doi.org/10.1038/s41467-025-59297-x |
| spellingShingle | Erina Sugita Nishimura Akihito Hishikawa Ran Nakamichi Riki Akashio Shunsuke Chikuma Akinori Hashiguchi Norifumi Yoshimoto Eriko Yoshida Hama Tomomi Maruki Wataru Itoh Shintaro Yamaguchi Jun Yoshino Hiroshi Itoh Kaori Hayashi DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages Nature Communications |
| title | DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages |
| title_full | DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages |
| title_fullStr | DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages |
| title_full_unstemmed | DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages |
| title_short | DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages |
| title_sort | dna damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages |
| url | https://doi.org/10.1038/s41467-025-59297-x |
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