DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation
Ran Nakamichi, Akihito Hishikawa, Shunsuke Chikuma, Akihiko 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
Abstract
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.