Cyclin-dependent kinase inhibitor p18INK4c is involved in protective roles of heme oxygenase-1 in cisplatin-induced acute kidney injury

Abstract

Experimental studies have demonstrated the protective effect of heme oxygenase (HO)-1 and cyclin-dependent kinase inhibitors (CDKIs) in acute kidney injury (AKI), and it has been documented that some of the protective effect of HO-1 is mediated by CDKIs. However, the role of p18INK4c (p18), an inhibitor of CDK4 (INK4), which is a family member of CDKIs, has not been well characterized in kidney diseases. The aim of the present study was to demonstrate p18 protection from the relationship between p18 and HO-1 in cisplatin-induced AKI. Upregulation of p18 and HO-1 was demonstrated by quantitative polymerase chain reaction (qPCR) and western blotting in cisplatin-induced AKI in vitro and in vivo. The effect of HO-1 on p18 was determined by western blotting using the inducer and inhibitor of HO-1 in vitro. The potential effect of p18 on HO-1 in cisplatin-induced AKI was examined by p18 gene knockout mice in vivo. The results showed that p18 and HO-1 were upregulated in cisplatin-induced AKI in vitro and in vivo. Deletion of the p18 gene did not affect the basal and inducible expression of HO-1 in the AKI animals, while hemin (10 μM) and znpp (10 μM), the inducer and inhibitor, respectively, of HO-1, regulated p18 expression when incubated with the cells. The results indicated that p18 may play protective roles and may be associated with or partially account for the cytoprotective effects of HO-1 in cisplatin-induced AKI.