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

急性肾损伤缺氧诱导因子的上下游机制

• 批准号: 192653319
• 负责人: Professor Dr. Michael Fähling
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/192653319?language=en
• 关键词: Mechanisms; Up; Down; Stream; Hypoxia

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.

目前，对于发展中的或确定的急性肾损伤（阿基），没有特异性治疗。局部肾血流动力学改变在阿基中起重要作用。最近的研究，包括我们小组的研究，表明缺氧诱导转录因子（HIF）的激活可以减轻实验性阿基。这些研究大多采用肾动脉阻断法诱导缺血再灌注损伤（I/RI）。重要的是，HIF激活通常在阿基发作之前实现。尚未研究对肾脏血流动力学的潜在影响。在转基因小鼠的初步研究中，我们发现，通过诱导敲除的von Hippel Lindau蛋白（pVHL），开始4周前的侮辱，激活HIF，增强肾小管间质毛细血管化和改善急性肾小管损伤实验性横纹肌溶解症。横纹肌溶解症模型非常类似于由挤压损伤诱导的阿基的人类综合征。在目前的提议中，我们试图研究1）在损伤发生之前或甚至之后不久，HIF激活是否可以实现肾保护，2）哪些HIF靶基因与阿基保护相关，3）改善的毛细血管化对肾保护的贡献，4）新型非侵入性磁共振成像技术用于早期诊断、风险分层、5）肌红蛋白和HIF对肾小球血流动力学的影响。总之，本研究将评估HIF激活在临床代表性阿基小鼠模型中的治疗潜力。

项目成果

Selective endothelin inhibition in diabetic nephropathy: is it the icing on the cake?

糖尿病肾病的选择性内皮素抑制：是锦上添花吗？

• DOI: 10.1111/apha.12332
• 发表时间: 2014
• 期刊: Acta Physiologica
• 影响因子: 6.3
• 作者: Rosenberger C;Fähling M
• 通讯作者: Fähling M

Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor.

• DOI: 10.1038/ki.2014.362
• 发表时间: 2015-04
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: M. Khamaisi;Hala Toukan;J. Axelrod;C. Rosenberger;G. Skarzinski;A. Shina;R. Meidan;R. Koesters;S. Rosen;G. Walkinshaw;I. Mimura;M. Nangaku;S. Heyman

Cyclosporin a induces renal episodic hypoxia

• DOI: 10.1111/apha.12811
• 发表时间: 2017-03-01
• 期刊: ACTA PHYSIOLOGICA
• 影响因子: 6.3
• 作者: Fahling, M.;Mathia, S.;Rosenberger, C.
• 通讯作者: Rosenberger, C.