Wang Liang, Zhang Yi, Yuan Li, Liu Chunyan, Fu Lili, Mei Changlin
Department of Urology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116021, P.R. China.
Department of Nephrology, Changzheng Hospital, Shanghai 200003, P.R. China.
Int J Mol Med. 2014 Sep;34(3):911-7. doi: 10.3892/ijmm.2014.1828. Epub 2014 Jul 1.
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.
实验研究已证明血红素加氧酶（HO）-1和细胞周期蛋白依赖性激酶抑制剂（CDKIs）在急性肾损伤（AKI）中的保护作用，并且有文献记载HO-1的部分保护作用是由CDKIs介导的。然而，CDKIs家族成员CDK4的抑制剂p18INK4c（p18）在肾脏疾病中的作用尚未得到充分阐明。本研究的目的是通过在顺铂诱导的AKI中研究p18与HO-1之间的关系来证明p18的保护作用。通过定量聚合酶链反应（qPCR）和蛋白质印迹法在体外和体内顺铂诱导的AKI中证实了p18和HO-1的上调。在体外使用HO-1的诱导剂和抑制剂通过蛋白质印迹法确定HO-1对p18的影响。在体内通过p18基因敲除小鼠研究了p18在顺铂诱导的AKI中对HO-1的潜在作用。结果表明，在体外和体内顺铂诱导的AKI中p18和HO-1均上调。p18基因的缺失不影响AKI动物中HO-1的基础表达和诱导表达，而HO-1的诱导剂血红素（10 μM）和抑制剂锌原卟啉（znpp，10 μM）与细胞孵育时可调节p18的表达。结果表明，p18可能发挥保护作用，并且可能与HO-1在顺铂诱导的AKI中的细胞保护作用相关或部分解释该作用。
