CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury.

Abstract

Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or "pharmacological quiescence," represents a novel strategy to prevent AKI.

• Authors: Derek P DiRocco, John Bisi, Patrick Roberts, Jay Strum, Kwok-Kin Wong, Norman Sharpless, Benjamin D Humphreys
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 306 Issue 4 Pg. F379-88 (Feb 15 2014) ISSN: 1522-1466 [Electronic] United States
• PMID: 24338822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Piperazines
• Pyridines
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Acute Kidney Injury (drug therapy, metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• DNA Damage (drug effects)
• Epithelial Cells (drug effects, metabolism)
• Humans
• Kidney Tubules, Proximal (drug effects, metabolism)
• Mice
• Piperazines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)