Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5231-6. doi: 10.1073/pnas.1424313112. Epub 2015 Apr 6.

Abstract

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.

Keywords: CDK4/6; acute kidney injury; cell cycle; cisplatin; organic cation transporters.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / pathology
  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use
  • Animals
  • Cell Cycle Checkpoints* / drug effects
  • Cisplatin
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kidney Tubules / drug effects
  • Kidney Tubules / enzymology
  • Kidney Tubules / pathology
  • Mice
  • Organic Cation Transport Proteins / antagonists & inhibitors*
  • Organic Cation Transport Proteins / deficiency
  • Organic Cation Transport Proteins / metabolism
  • Organic Cation Transporter 2
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use
  • Purines / pharmacology
  • Purines / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use

Substances

  • Aminopyridines
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Piperazines
  • Protective Agents
  • Purines
  • Pyridines
  • Slc22a2 protein, mouse
  • Small Molecule Libraries
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib
  • Cisplatin
  • ribociclib