Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a 
rapid decline in kidney function caused by ischemic or toxic injury to renal 
tubular cells. The widely used chemotherapy drug cisplatin accumulates 
preferentially in the renal tubular cells and is a frequent cause of 
drug-induced AKI. During the development of AKI the quiescent tubular cells 
reenter the cell cycle. Strategies that block cell-cycle progression ameliorate 
kidney injury, possibly by averting cell division in the presence of extensive 
DNA damage. However, the early signaling events that lead to cell-cycle 
activation during AKI are not known. In the current study, using mouse models of 
cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent 
kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry 
but before the development of AKI. Targeted inhibition of CDK4/6 pathway by 
small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) 
resulted in inhibition of cell-cycle progression, amelioration of kidney injury, 
and improved overall survival. Of additional significance, these compounds were 
found to be potent inhibitors of organic cation transporter 2 (OCT2), which 
contributes to the cellular accumulation of cisplatin and subsequent kidney 
injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and 
LEE011, combined with their potential for clinical translation, support their 
further exploration as therapeutic candidates for prevention of AKI.