Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

• Published in: The Journal of clinical investigation Vol. 132; no. 16; pp. 1 - 20
• Main Authors: Pippin, Jeffrey W, Kaverina, Natalya, Wang, Yuliang, Eng, Diana G, Zeng, Yuting, Tran, Uyen, Loretz, Carol J, Chang, Anthony, Akilesh, Shreeram, Poudel, Chetan, Perry, Hannah S, O'Connor, Christopher, Vaughan, Joshua C, Bitzer, Markus, Wessely, Oliver, Shankland, Stuart J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.08.2022
• Subjects: Age; Aged; Aging; Animals; Antibodies; Apoptosis; Biomedical research; Cell death; Cell survival; Creatinine; Development and progression; Endothelial cells; Endothelial Cells - metabolism; Glomerular filtration rate; Glomerulosclerosis, Focal Segmental - genetics; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulus; Health aspects; Humans; Immunity; Immunohistochemistry; Kidney diseases; Kidney Glomerulus - metabolism; Kidneys; Life span; Ligands; Liver; Mice; PD-1 protein; PD-L1 protein; Phenotypes; Physiological aspects; Podocytes - metabolism; Proteins; Proteinuria; Risk factors; Senescence; Signal Transduction; Socioeconomic factors; Transcriptomics; United States; United States > US; Aging; Chronic kidney disease; Expression profiling
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI156250

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti-PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti-PD-1 antibody treatment improved the health span of podocytes. Administering the same anti-PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.