Overexpression of p18 INK4C in LLC-PK1 cells increases resistance to cisplatin-induced apoptosis
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ORIGINAL ARTICLE
Overexpression of p18INK4C in LLC-PK1 cells increases resistance to cisplatin-induced apoptosis Yi Zhang & Li Yuan & Lili Fu & Chunyan Liu & Dongmei Liu & Changlin Mei
Received: 4 August 2010 / Revised: 10 March 2011 / Accepted: 17 March 2011 / Published online: 15 April 2011 # IPNA 2011
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. Y. Zhang : L. Yuan : L. Fu : C. Liu : D. Liu : C. Mei (*) Nephrology Department of Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China e-mail: [email protected]
Keywords Cyclin-dependent kinase inhibitor . p18 . Cisplatin . Transfection . Acute kidney injury
Introduction Although recent advances have improved our understanding of acute kidney injury (AKI), the mortality from AKI remains high, especially in patients in the intensive care unit, where mortality is higher than 50% [1]. The pathogenesis of AKI is complex, involving inflammation, cytokines, and multiple cell-death pathways [2–10]. AKI is thus a challenging clinical syndrome, although renal replacement therapy provides an effective supportive treatment for AKI patients. Necrosis and apoptosis are the main manifestations of AKI in both kidney injury in vivo and renal cell injury in vitro. Activation of cell-death pathways and the actions of cell-cycle regulatory proteins eventually decide the final fate of injured renal cells: proliferation, hypertrophy or apoptosis [11–13]. Cyclins bind to cyclin-dependent kinases (CDK) to form a complex that promotes cell-cycle progression [14], while cy
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