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

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.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)