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Significance of podocyte DNA damage and glomerular DNA methylation in CKD patients with proteinuria

Hypertension Research volume 46, pages 1000–1008 (2023)Cite this article

Abstract

The number of chronic kidney disease (CKD) patients is increasing worldwide, and it is necessary to diagnose CKD patients in earlier stages to improve their prognosis. Previously, in a study using human samples, we reported that DNA methylation and DNA damage in podocytes are potential markers for kidney function decline in IgA nephropathy; however, these candidate markers have not been adequately investigated in other glomerular diseases. Here, we report that the association of podocyte DNA damage and DNA methylation with eGFR decline and proteinuria differs depending on the type of glomerular disease. Patients diagnosed with minor glomerular abnormality (MGA, n = 33), membranous nephropathy (MN, n = 9) or diabetic nephropathy (DN, n = 10) following kidney biopsy at Keio University Hospital from 2015 to 2017 were included. In MGA patients, both podocyte DNA damage and glomerular DNA methylation were associated with the severity of proteinuria. In DN patients, podocyte DNA double-strand breaks (DSBs) and glomerular DNA methylation were associated with an eGFR decline. When patients with urinary protein levels of more than 1 g/gCr were examined, fewer podocyte DNA DSBs were detected in MN patients than in MGA patients, and the level of glomerular DNA methylation was lower in MN patients than in MGA or DN patients. These results indicate that investigating podocyte DNA DSBs and DNA methylation changes may be useful for understanding the pathogenesis of CKD with proteinuria in humans.

This study suggested the association of podocyte DNA damage and subsequent DNA methylation with proteinuria in minor glomerular abnormalities (MGA) patients and those with eGFR declines in diabetic nephropathy (DN) patients, respectively.

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Acknowledgements

We acknowledge Dr. Hideaki Nakaya for providing assistance during the initial stage of this study. This study was supported by Grants for Scientific Research (22H03091, 20H00535, and 19K08688) 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.

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Authors and Affiliations

  1. Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    Norifumi Yoshimoto, Kaori Hayashi, Akihito Hishikawa, Ran Nakamichi, Erina Sugita-Nishimura, Eriko Yoshida-Hama, Tatsuhiko Azegami, Takashin Nakayama & Hiroshi Itoh

  2. Department of Pathology, Keio University School of Medicine, Tokyo, Japan

    Akinori Hashiguchi

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  1. Norifumi Yoshimoto
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Contributions

NY performed the experiments, analyzed the data, and wrote the manuscript. KH conceived and designed the research study, analyzed, and interpreted the data, and wrote the manuscript. AHa supported the pathological evaluations and revised the manuscript. AHi, RN, ES, EY, TA and TN contributed to the drafting and revision of the manuscript. HI supervised the entire project and edited the manuscript.

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Correspondence to Kaori Hayashi.

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Yoshimoto, N., Hayashi, K., Hishikawa, A. et al. Significance of podocyte DNA damage and glomerular DNA methylation in CKD patients with proteinuria. Hypertens Res 46, 1000–1008 (2023). https://doi.org/10.1038/s41440-023-01169-2

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