The Intersection of Podocyte Disease and Aging

点击翻译按钮获取中文摘要

The scope of the problem is that kidney diseases become more abundant as the US population lives longer. In particular, the risk, incidence, and prevalence of CKD increases with age. As a result, disease severity is higher in elderly patients, the largest group to undergo first-time chronic dialysis. Injury to podocytes remains the primary cause for glomerulosclerosis in both aging and disease. Yet, understanding the intersection of podocyte injury and aging, and the underlying mechanisms responsible are a major unmet need. To close this knowledge gap, our pilot studies showed that podocyte injury in young mice from two models of experimental Focal Segmental Glomerulosclerosis (FSGS) unexpectedly induces short-term replicative- and stress-induced premature senescence. In the long-term this results in premature podocyte aging in early middle-aged mice, which under healthy conditions typically do not exhibit signs of senescence and aging. This phenotype was accompanied by glomerulosclerosis and a reduced kidney function. Finally, the same correlations were also observed in young patients with FSGS. Based on these preliminary data, we propose a novel paradigm that podocyte injury and aging intersect, and because of these overlapping mechanisms, injury amplifies aging. The overall goal of this proposal is to identify novel mechanisms for podocyte injury progression with advancing age. Specific Aim #1 will prove that injury to podocytes causes a premature aging podocyte phenotype. This will be achieved by testing the following hypotheses: (i) Injury to non-aged podocytes causes a p16-dependent replicative senescence and an aged phenotype; (ii) Injury to young podocytes causes a p53- p21 axis-dependent stress-induced premature senescence; (iii) Long-term consequences of injury-induced senescence is a premature podocyte aging phenotype causing glomerular scarring and reduced kidney function. Specific Aim #2 will prove that the mechanisms of podocyte injury and that of aging intersect/overlap and are amplified when superimposed on one another. We will test the following hypotheses: (i) Distinct subpopulations of podocytes are responsible for the intersection between injury and aging; (ii) A combination of inflammatory cytokines, immune modulators and growth factors secreted as a result of the senescent- associated secretory phenotype triggered by podocyte injury promotes disease progression. Innovative experimental approaches used include two models of podocyte injury, loss-of-function approaches using four new podocyte-specific mouse mutants to limit podocyte senescence/ aging, gain-of- function approaches using two new podocyte-specific transgenic mice, single nuclei transcriptomics of injured podocytes over time and the Design-of-Experiment methodology to holistically explore the podocyte signaling environment. The proposal is significant for its short-term translational impact by integrating our mouse data with large transcriptomic data sets from aged and diseased human kidneys and for its long-term impact in developing new strategies to counter the age-dependent demise of kidney function from disease.