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

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

Author information

1
Departments of Pharmaceutical Sciences.
2
Chemical Biology & Therapeutics, and.
3
Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
4
Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty, 48149 Münster, Germany.
5
Departments of Pharmaceutical Sciences, alex.sparreboom@stjude.org.

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

PMID:
25848011
PMCID:
PMC4413320
DOI:
10.1073/pnas.1424313112
[Indexed for MEDLINE]
Free PMC Article

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