SIRT1 过表达可降低顺铂诱导的肾近端小管细胞 NF-κB p65 亚单位乙酰化和细胞毒性。
SIRT1 overexpression decreases cisplatin-induced acetylation of NF-κB p65 subunit and cytotoxicity in renal proximal tubule cells.
机构信息
Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, South Korea.
出版信息
Biochem Biophys Res Commun. 2012 Mar 9;419(2):206-10. doi: 10.1016/j.bbrc.2012.01.148. Epub 2012 Feb 5.
As the increased acetylation of p65 is linked to nuclear factor-κB (NF-κB) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-κB and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-κB and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-κB p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-κB during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-κB p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-κB through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.
由于 p65 的乙酰化增加与核因子-κB（NF-κB）的激活有关，因此 p65 乙酰化的调节可能是治疗炎症损伤的潜在靶点。顺铂诱导的肾毒性是癌症患者化疗中的一个重要问题。SIRT1，烟酰胺腺嘌呤二核苷酸（NAD(+))-依赖性蛋白去乙酰化酶，与多种细胞过程有关，如炎症损伤和癌症的多药耐药性的控制。然而，目前尚无关于 SIRT1 过表达对顺铂诱导的 NF-κB p65 亚单位乙酰化和细胞损伤的影响的报道。为了研究 SIRT1 对顺铂诱导的 NF-κB p65 亚单位乙酰化和细胞损伤的影响，在用顺铂处理后，HK2 细胞暴露于 SIRT1 过表达、LacZ 腺病毒或显性负性腺病毒中。与对照缓冲液处理相比，顺铂处理后 SIRT1 的蛋白表达减少，但 NF-κB p65 亚单位的乙酰化明显增加。SIRT1 的过表达改善了顺铂处理过程中 NF-κB p65 的乙酰化增加，并减轻了顺铂诱导的 HK2 细胞毒性。此外，用 SIRT1 激活剂白藜芦醇处理顺铂处理的 HK2 细胞，也降低了 NF-κB p65 亚单位的乙酰化，并降低了顺铂诱导的 HK2 细胞活力的增加。我们的研究结果表明，通过 SIRT1 调节 NF-κB p65 的乙酰化可能是减轻顺铂诱导的肾细胞损伤的一个潜在靶点。
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