title: Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions.
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.
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Mike
authors.initials: M
authors.lastname: Buege
authors.affiliation: Chemical Biology & Therapeutics, and.
authors.forename: Su Sien
authors.initials: SS
authors.lastname: Ong
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Du
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Sprowl
authors.affiliation: Departments of Pharmaceutical Sciences.
authors.forename: Aksana
authors.initials: A
authors.lastname: Vasilyeva
authors.affiliation: Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty, 48149 Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
authors.affiliation: Chemical Biology & Therapeutics, and.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.affiliation: Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty, 48149 Münster, Germany.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.affiliation: Departments of Pharmaceutical Sciences, alex.sparreboom@stjude.org.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002945:Cisplatin; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000631:Aminopyridines; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D010879:Piperazines; D020011:Protective Agents; D011687:Purines; D011725:Pyridines; C491012:Slc22a2 protein, mouse; D054852:Small Molecule Libraries; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib; D002945:Cisplatin; C000589651:ribociclib
keywords: CDK4/6; acute kidney injury; cell cycle; cisplatin; organic cation transporters
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