Mechanisms Up- and Down-Stream of Hypoxia-Inducible Factor in Acute Kidney Injury

目前，对于进展性或已确诊的急性肾损伤(AKI)尚无特效治疗方法。局部肾血流动力学改变在AKI中起重要作用。最近的研究，包括我们小组的研究表明，激活低氧诱导的转录因子(HIF)可以缓解实验性AKI。这些研究大多采用肾动脉夹闭的方法诱导缺血再灌注损伤(I/RI)。重要的是，HIF的激活通常是在AKI发生之前实现的。对肾脏血流动力学的潜在影响还没有研究。在转基因小鼠的初步研究中，我们发现，在实验性横纹肌溶解中，通过诱导敲除von Hippel Lindau蛋白(PVHL)激活HIF，从损伤前4周开始，可以增强肾小管间质毛细血管形成，并改善急性肾小管损伤。横纹肌溶解症模型与挤压伤所致的人类AKI综合征非常相似。在本研究中，我们试图探讨1)在急性肾损伤发生之前或之后激活HIF是否可以实现肾脏保护，2)哪些HIF靶基因与AKI的保护有关，3)改进的毛细血管形成对肾脏保护的贡献，4)新的无创性磁共振成像技术在AKI早期诊断、风险分层和控制HIF激活治疗中的潜在作用，5)肌红蛋白和HIF对肾小球血流动力学的影响。综上所述，这项研究将评估HIF激活在具有临床代表性的AKI小鼠模型中的治疗潜力。

At present, no specific therapy exists for either evolving or established acute kidney injury (AKI). Altered regional renal hemodynamics play an important role in AKI. Recent studies, including those from our group, suggest that activation of hypoxia-inducible transcription factors (HIFs) can alleviate experimental AKI. Most of these studies used renal artery clamping to induce ischemia and reperfusion injury (I/RI). Importantly, HIF activation was commonly achieved before the onset of AKI. The potential impact on renal hemodynamics has not been studied. In a preliminary study in transgenic mice, we found that activation of HIF through an inducible knockout of the von Hippel Lindau protein (pVHL), starting 4 wk before the insult, enhances renal tubulo-interstitial capillarization and ameliorates acute tubular injury in experimental rhabdomyolysis. The rhabdomyolosis model closely resembles the human syndrome of AKI induced by crush injury. In the present proposal, we attempt to investigate 1) whether renal protection may be achieved with HIF activation shortly before or even after the onset of injury, 2) which HIF target genes associate with protection from AKI, 3) the contribution of improved capillarization to renal protection, 4) the potential role of novel non-invasive magnetic resonance imaging techniques for early diagnose, risk stratification, and control of HIF activating therapy in AKI, 5) the effects of myoglobin and HIF on glomerular hemodynamics. Taken together, this study will evaluate the therapeutic potential of HIF activation in a clinically representative mouse model of AKI.