Mechanisms of Successful vs. Failed Kidney Repair

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ABSTRACT Outcomes after acute kidney injury (AKI) cover a wide spectrum ranging from full recovery to failed repair and transition to chronic kidney disease. Medicare patients aged 66 years and older who were hospitalized for AKI had a 35% cumulative probability of a recurrent AKI hospitalization within one year and 28% developed chronic kidney disease (CKD) in the year following hospitalization (the “AKI to CKD transition”). Work from our laboratory and others has demonstrated that proximal tubule repairs through injury-induced dedifferentiation of mature proximal tubule cells. A cardinal feature of proximal tubule dedifferentiation is increased proliferative capacity, but the mechanisms governing this process are incompletely understood. Moreover, in cases of severe or repetitive injury, proximal tubule epithelia become arrested in the G2/M phase of the cell cycle, leading to profibrotic cytokine secretion, tubulointerstitial fibrosis and CKD. The long term goal of this application is to define the molecular mechanisms of proximal tubule cell cycle progression and test whether this can be manipulated to promote successful repair. We have identified the specific and strong upregulation of the transcription factor forkhead box protein M1 (FoxM1) in injured proximal tubule after injury with subsequent downregulation by day 14. FoxM1 drives transcription of proliferation-related genes, and regulates both G1/S and G2/M phases of the cell cycle. We show that the epithelial growth factor receptor (EGFR) regulates FoxM1 expression both in vitro and in vivo, and knockdown of FoxM1 in primary renal proximal tubule epithelial cells (RPTECs) inhibits cell proliferation. EGFR activation in proximal tubule is also known to activate Yes-Associated Protein (Yap) and Tea Domain transcription factors (TEAD) which in turn regulates cell proliferation after AKI. Based on published and preliminary data, we propose that AKI leads to EGFR- dependent upregulation of FoxM1 via AKT and Yap/TEAD, causing pro-repair proximal tubule proliferation. We further hypothesize that failed repair and profibrotic G2/M arrest in proximal tubule can be prevented by inducible FoxM1 expression, driving a G2 transcriptional program, cell cycle progression and successful repair. In Aim 1 we examine the roles of EGFR, Hippo and FoxM1 signaling networks in proximal tubule epithelia. In Aim 2, we define the role of FoxM1 in successful repair after ischemia-reperfusion injury using a conditional deletion strategy. In Aim 3 we ask whether tubule-specific, transient expression of constitutively active FoxM1 (FoxM1∆N) can rescue pro-fibrotic G2/M cell cycle arrest and failed repair.