Cellular Senescence and the AKI to CKD transition

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) has a rising incidence among hospitalized patients and the risk for progression to chronic kidney disease (CKD) has been established in both pre-clinical and clinical studies; however, there is still a knowledge gap on the molecular mechanisms driving the AKI to CKD transition. We previously identified Foxm1, a transcription factor considered to be a master regulator of the cell cycle, as having a role in tubular epithelial proliferation in a mouse model of acute ischemic renal injury, Subsequent studies using genetic deletion mouse models demonstrated that Foxm1 is involved in proximal tubular epithelial proliferation after injury in vivo. Furthermore, impaired tubular proliferation due to Foxm1 deletion led to an early AKl-to-CKD transition phenotype highlighting its pro-repair role; however, the exact mechanism for the profibrotic effect of Foxm1 deletion is unclear. Our recent in vitro work has identified a novel Foxm1 target mediating proliferation - the cyclin family membercyclin F (CCNF), CCNF is a gene with a role in cell cycle progression and genome stability, Induction of cell cycle arrest and genome instability have been described to promote the development of cellular senescence. In preliminary studies, we observed that expression of cell senescence markers and components of the senescence secretory phenotype (SASP) correlate with repression of Foxm1 induction after injury suggesting that Foxm1 deletion may be driving increased cellular senescence. This let us to hypothesize that (1) Tubular epithelial cells that failed to repair undergo cellular senescence which drives the AKI to CKD transition and (2) this process is mediated by downregulation of the Foxm1-CCNF axis inducing cell cycle arrest and genome instability, In Aim 1, we will characterize how Foxm1 repression during tubular epithelial repair leads to cellular senescence and in turn transition to CKD. In Aim 2, we will determine if CCNF repression triggers the transition to cellular senescence and identify potential downstream pathways, In this application we aim to understand how alterations in the pro-repair effects of Foxm1 lead to unsuccessful repair and development of cellular senescence with the goal of identifying areas for therapeutic interventions through senolytics (cell senescence removal) or senomorphics (suppress the SASP),