Graphical abstract of the study. DNA double-strand breaks (DSBs) in kidney glomerular podocytes cause increased DNA methylation in genes critical for podocyte morphology, such as nephrin and podocin, leading to disruption of the slit membrane and proteinuria. Podocyte DNA DSBs also promote interferon (IFN)-stimulated gene expressions, inducing MHC class I and NKG2D ligand expression in podocytes, which activates and differentiates CD8+T cells. The activated T cells attack podocytes directly, leading to podocyte loss and glomerulosclerosis. Furthermore, exosomes originating from damaged podocytes containing DNMT mRNA may contribute to proliferation of naive CD8+T cells through alteration of DNA methylation in STAT1-binding sites, which leads to expansion of memory T cells. The memory CD8+T cells in peripheral blood and bone marrow (BM) could cause sustained inflammation and renal fibrosis, maintained by IL-7 produced in BM stroma cells.
