Prolonged depletion of renal tubular thioredoxin following severe acute kidney injury is associated with transition to chronic kidney disease via G2/M cell cycle arrest.

Acute kidney injury (AKI) is a potentially life-threatening event, particularly when there is transition from AKI to chronic kidney disease (CKD). Thioredoxin (TRX) is a key regulator of the intracellular redox environment. Among its redox-sensitive target proteins is the G2/M cell cycle regulator cell division cycle 25 C (Cdc25C). After AKI, tubular TRX levels are decreased, while urinary levels are increased. The aim of this study was to investigate the impact of tubular TRX depletion on AKI-to-CKD transition in mouse models of mild and severe AKI and in renal epithelial cell lines. Mice with severe AKI from reperfusion after 30 min of ischemia showed prolonged tubular TRX depletion with increased urinary TRX excretion and impaired TRX mRNA synthesis. After mild AKI (10 min-ischemia and reperfusion), urinary TRX excretion was limited and tubular TRX levels quickly recovered with marked TRX mRNA synthesis. In mice with severe AKI, phosphorylation and cytoplasmic translocation of Cdc25C and cell cycle arrest at G2/M phase were observed. In addition, levels of the profibrotic factors transforming growth factor beta and connective tissue growth factor were increased, suggesting progression of AKI-to-CKD transition. Treatment with TRX inducers or TRX overexpression ameliorated AKI-induced Cdc25C-mediated G2/M arrest and progression of AKI-to-CKD transition. Redox-dependent G2/M arrest and increased levels of profibrotic factors were also observed in renal epithelial cells after treatment with TRX reductase inhibitors or TRX knockdown. These findings suggest that tubular TRX depletion after severe AKI is associated with redox-dependent G2/M arrest and progression of AKI-to-CKD transition.