p18^(INK4C)基因敲除加重顺铂诱导的小鼠急性肾损伤

p18^(INK4C) depletion aggravates cisplatin-induced acute kidney injury in mice

目的探讨周期素依赖性激酶抑制基因p18INK4C敲除对顺铂诱导的小鼠急性肾损伤(AKI)的影响,并分析其可能机制。方法利用已引种的杂合p18INK4C基因敲除小鼠p18INK4C+/-繁育p18INK4C基因敲除小鼠p18INK4C-/-(KO组),以同窝野生型小鼠p18INK4C+/+作为对照(WT组),腹腔注射顺铂制备AKI模型,观察两组小鼠的存活情况,并检测给药后第2、3、5天血肌酐、尿素氮的变化及肾组织的病理变化。结果WT组小鼠在第3天出现死亡,第7天存活率为46.7%(14/30)。KO组小鼠自第2天出现死亡,至第7天全部死亡(100.0%,30/30)。KO组的死亡率显著高于WT组(P<0.05)。自给药后第2天起,KO组小鼠的肾功能恶化明显,此后继续加重。给药后第2、3、5天,KO组的尿素氮、肌酐均显著高于WT组(P值均<0.05)。WT和KO组小鼠均以给药后第3天肾脏病变最为严重。结论p18INK4C基因敲除加速了顺铂诱导的小鼠AKI的进展,可能与其增加小管上皮损伤及加剧炎性反应有关。

Objective To investigate the effect of depletion of p18^INK4c, a cyclin dependent kinase inhibitor, on cisplatin-induced nephrotoxicity and to explore the possible mechanism. Methods p18^INK4c-/- （KO group） and p18^INK4c ＋/4- （WT group） mice were generated from heterozygous mice, p18^INK4c ＋/-, breeding pairs, purchased from University of Pittsburgh. Acute renal failure model was induced by intraperitoneal injection of cisplatin. The survival statuses of mice in the two groups were observed. The mice were sacrificed at 2, 3 and 5 days after the cisplatin injection to observe the renal function （creatinine and urea nitrogen） and morphological changes. Results The mice in WT group began to die on the 3rd day; the survival rate on the 7th day was 46.7% （14/30）. Mice in KO group began to die on the 2nd day, and all died on the 7th day. Compared with the knockout mice, the survival time of mice in the control group was significantly prolonged （P〈0.05）. Severe renal function damage was observed in the KO group on 2, 3 and 5 days after the administration of cisplatin. The worst histological change took place on day 3. Conclusion p18^INK4c depletion accelerates the pathogenesis of cisplatin-induced acute renal failure in mice, which might be related to the aggravated tubular damage and inflammatory response. （Shanghai Med J, 2009, 32 ： 188-190）