Podocyte Aging with and without Hypertension: A Comparative Study in Young and Middle-Aged Mice

Recent studies show that acute injury to non-aged podocytes induces many similarities to healthy aged podocytes, such as decreased lifespan and health-span. Like healthy aged podocytes, injury to young mouse and human podocytes can induce a senescent phenotype. This begs the question if injury to young podocytes phenocopies a healthy middle-aged podocyte, and if the pathways underlying senescence and other injury responses overlap between injured young podocytes and healthy middle-aged podocytes. To address this knowledge gap we induced hypertension, a major cause of chronic kidney disease, in young mice (4m of age~20-year-old human) and in middle-aged mice (18m of age, ~55+ year old human) with deoxycorticosterone and high salt (DOCA) and compared outcomes to non-hypertensive healthy middle-aged mice. In both healthy middle-aged mice and in young mice with hypertension, the increase in age-related senescent genes p16 and p19, along with the stress-related senescent genes p21 and p53 were similar. Bulk RNA-sequencing of podocytes showed that the senescent associated secretory phenotype and individual genes from several aging gene sets were also similar between middle-aged mice and young mice with hypertension. Of the highest enriched Hallmark pathways in middle-aged podocytes, 95% were also enriched in young mice treated with DOCA. Gene set enrichment analysis of podocytes showed that 36 genes overlapped between middle-aged mice, and young and middle-aged mice given DOCA, while 119 genes identified were “DOCA-specific”. These results suggest that hypertension in young mice induces podocyte injury and an aging/senescent phenotype that is similar to the one of podocytes from healthy middle-aged mice.