背景:缺血再灌注(IR)引起的急性肾损伤(AKI)是临床上严重且频繁的并发症,死亡率仍然很高。肾脏IR存在公认的性别差异,与女性相比,男性在缺血性损伤后表现出更大的损伤。我们最近报道,男性缺血性损伤与肾脏恢复受损。femals.然而,介导IR损伤后肾脏恢复的性别差异的机制仍知之甚少.据报道,12/15脂氧合酶(LOX)活性升高有助于许多肾脏疾病的进展。当前研究的目标是检验以下假设:12/15LOX的增强激活有助于男性与男性的IR后恢复受损femals.
方法:将13周龄雄性和雌性自发性高血压大鼠(SHR)随机进行假手术或30分钟热双侧IR手术。其他男性和女性SHR在假手术/IR手术前1小时随机接受媒介物或特定的12/15LOX抑制剂ML355治疗。并且在IR后的7天之后每隔一天。在IR后1天和7天从所有大鼠收集血液。肾脏在IR后7天收获,并进行生化处理,组织学,和蛋白质印迹分析。通过液相色谱-质谱(LC/MS)测定肾样品中的12/15LOX代谢物12和15HETE。
结果:男性SHR表现出IR后肾功能延迟恢复与雄性假IR大鼠和雌性IR大鼠。男性的延迟恢复与肾脏12/15LOX的激活有关,增加肾12-HETE,增强的内质网(ER)应激,脂质过氧化,与IR后7天的女性相比,肾细胞死亡和炎症。用ML355治疗男性SHR降低了12-HETE的水平,并导致肾脏脂质过氧化降低,ER压力,与媒介物处理的IR雄性大鼠相比,IR后7天肾小管细胞死亡和炎症,肾功能恢复增强。ML355治疗没有改变IR诱导的女性血浆肌酐增加,然而,与载体处理的大鼠相比,在IR后7天,ML355处理的雌性中的肾小管损伤和细胞死亡减弱。
结论:我们的数据表明,在男性和女性SHR中,持续激活12/15LOX有助于缺血性损伤后肾脏恢复受损,尽管男性比女性更容易受到这种机制的影响。
BACKGROUND: Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females.
METHODS: 13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography-mass spectrometry (LC/MS).
RESULTS: Male SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR.
CONCLUSIONS: Our data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.