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

Ran Nakamichi1, Akihito Hishikawa1, Shunsuke Chikuma2

  • 1Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.

Cell Reports
|March 29, 2023
PubMed

Insights

Podocyte DNA damage in the kidneys causes kidney disease and alters blood DNA methylation. This leads to changes in cytotoxic CD8+ T cells, contributing to chronic kidney injury.

Area of Science:

  • Nephrology
  • Immunology
  • Epigenetics

Background:

  • Epigenome-wide studies link blood DNA methylation to kidney function.
  • The pathological role of these methylation changes in kidney disease is not fully understood.

Purpose of the Study:

  • To investigate the pathological importance of DNA damage in kidney podocytes and its link to blood DNA methylation and immune cell changes.
  • To explore the role of CD8+ T cells and NKG2D in kidney injury.

Main Methods:

  • Induction of DNA double-strand breaks in kidney glomerular podocytes using I-PpoI.
  • Single-cell RNA-sequencing analysis of kidney and peripheral blood cells.
  • NKG2D blockade experiments.
  • Analysis of blood methylome and STAT1 binding sites.

Main Results:

  • Podocyte DNA damage induced proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis.
  • Increased cytotoxic CD8+ T cells with NKG2D expression in kidneys and CD44high memory CD8+ T cells in circulation.
  • NKG2D blockade ameliorated kidney damage.
  • Blood methylome showed increased DNA methylation in STAT1 binding sites.

Conclusions:

  • Podocyte DNA damage triggers epigenetic alterations in blood DNA methylation.
  • These epigenetic changes promote CD8+ T cell activation and contribute to sustained renal injury in chronic kidney disease.
Keywords:
CP: ImmunologyCP: Molecular biologyDNA damageDNA methylationchronic kidney diseasepodocyte

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