Upregulated PD-1 Signaling Is an Important Antagonist to Glomerular Health in Aged Mouse Kidneys

Kidney aging and its contribution to disease and its underlying mechanisms are not well understood. Yet with an aging population, kidney health becomes an important medical and socioeconomic factor. We previously showed that podocytes isolated from aged mice exhibit increased expression of Programed Cell Death Protein 1 (PD-1) surface receptor and its two ligands (PD-L1, PD-L2). We now extend this observation to aged human kidneys. In vitro studies in cultured podocytes demonstrate a critical role of PD-1 signaling in cell survival and the induction of a Senescence-Associated Secretory Phenotype (SASP). To prove that the PD-1 signaling is critical to podocyte aging, aged mice were injected with an anti-PD-1 antibody (aPD-1ab). This treatment significantly improved the aging phenotype of the kidney and liver. In the glomerulus, it increased the lifespan of podocytes, but not parietal epithelial, mesangial or endothelial cells. Moreover, transcriptomic and immunohistochemistry studies demonstrate that anti-PD-1 treatment also improved the health-span of podocytes. It restored the expression of canonical podocyte genes, transcription factors and gene regulatory networks, increased the cellular metabolism signatures and lessened the SASP of aged podocytes. Increased PD-1 transcripts in human glomeruli significantly correlated with reduced eGFR.Together, these results suggest a critical contribution of increased PD-1 signaling towards both kidney and liver aging. We did RNA-seq of podocytes from young (4-month-old) mice, old mice(21-month-old) treated with PD1 control antibody, and old mice treated with anti-PD1 antibody. All mice were male. We have 5 biological replicates per condition