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

Abstract

Kidney aging and its contribution to disease and its underlying mechanisms are not well understood. 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). PDCD1 transcript increases with age in micro-dissected human glomeruli, which correlates with lower eGFR, and higher segmental glomerulosclerosis and vascular arterial intima to lumen ratio. In vitro studies in podocytes demonstrate a critical role for PD-1 signaling in cell survival and induction of a Senescence-Associated Secretory Phenotype (SASP). To prove PD-1 signaling is critical to podocyte aging, aged mice were injected with anti-PD-1 antibody (aPD-1ab). Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life-span of podocytes, but not parietal epithelial, mesangial or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrate that anti-PD-1 treatment improved the health-span of podocytes. It restored the expression of canonical podocyte genes, transcription factors and gene regulatory networks, increased cellular metabolism signatures and lessened SASPs. These results suggest a critical contribution for increased PD-1 signaling towards both kidney and liver aging.

Compartmentalization of Intrarenal Programmed Cell Death Protein 1-Ligand 1 and Its Receptor in Kidney Injury Related to Immune Checkpoint Inhibitor Nephrotoxicity

“…Tubular PD-L1 positivity was predominantly found in proximal tubular epithelial cells as previously described ( 12 , 13 ). Glomerular PD-L1 was found in parietal epithelial cells and podocytes, again in line with previous reports ( 14 ). Among potential mechanisms, tubular PD-L1 positivity was positively correlated with systemic inflammation (elevated serum levels of CRP), in line with previous investigations reporting CRP serum elevation to reflect irAE onset including kidney involvement ( 15 , 16 ).…”

N6-methyladenosine participates in mouse hippocampus neurodegeneration via PD-1/PD-L1 pathway

“…In AD patients and mouse models, PD-1 expression was upregulated in astrocytes and microglia (Kummer et al, 2021). In addition, a recent study found that enhanced expression of PD-1 was highly correlated with reduced kidney function in aging humans (Pippin et al, 2022). In our study, PD-1/ PD-L1 pathway activity was significantly enhanced in the aging (64-week-old) hippocampus at both the methylation and transcriptional levels.…”