title: Overexpression of p18INK⁴C in LLC-PK1 cells increases resistance to cisplatin-induced apoptosis.
abstract: Studies have demonstrated that cyclin-dependent kinase inhibitors (CDKI) that inhibit cell-cycle progression have a protective effect against acute kidney injury (AKI). Most studies have focused on the CIP/KIP family members of CDKI; only a few have explored the role of INK4 family members in AKI. Because INK4 family members block the G1-S transition, we postulated that they should have protective effects against AKI. The most conserved INK4 member is p18, so we selected it to explore its effects on cisplatin-induced renal cell injury. We overexpressed p18 in renal tubular epithelial cells (LLC-PK1) by transient transfection and investigated its effects on the cell cycle and proliferation. After transfection, cell injury was induced by cisplatin (100 μM) incubation for 24 h in a standard medium. The effect of p18 was assayed by assessing cell necrosis and apoptosis in transfected cells. The endoplasmic reticulum stress (ERS) pathway was evaluated to interpret the possible mechanism of p18 action in cisplatin-induced renal cell injury. Overexpression of p18 arrested cell cycle progression in the G1 phase and inhibited proliferation. Compared with vehicle transfection, p18 overexpression did not affect cisplatin-induced necrosis, but it reduced the percentage of apoptotic cells significantly. The severity of ERS induced by cisplatin was also decreased by p18 overexpression. P18 protects against cisplatin-induced renal cell injury. The mechanism of p18 protection may lie in its effect on the cell death pathway.
authors.affiliation: Nephrology Department of Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.forename: Lili
authors.initials: L
authors.lastname: Fu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Dongmei
authors.initials: D
authors.lastname: Liu
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002469:Cell Separation; D002945:Cisplatin / Q000494:pharmacology*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine; D014162:Transfection
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D002945:Cisplatin