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Transient receptor potential vanilloid type 1 (TRPV1) channels in acute kidney injury

急性肾损伤中瞬时受体电位香草酸 1 型 (TRPV1) 通道

基本信息

批准号：
192637660
负责人：
Professor Dr. Maik Gollasch
金额：
--
依托单位：
Klinik und Poliklinik für Innere Medizin D - Geriatrie
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 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/192637660?language=en
关键词：
Transient receptor potential vanilloid type

项目摘要

The transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated non selective cation channel that can be activated by endogenous substances including 20-hydroxyeicosatetraenoic acid (20-HETE) and exogenous substances including capsaicin, the pungent ingredient of red chilli pepper. We hypothesize that TRPV1 channels play crucial roles in ischemic AKI by modulating renal blood flow. TRPV1 channels and their natural activator 20-HETE may also contribute to vascular and tubular repair processes that allow a recovery of renal function after ischemia/reperfusion (I/R) -induced injury. Recent literature and own preliminary results indeed suggest an important role of TRPV1 channels and 20-HETE in the regulation of vascular tone in the setting of renal I/R injury, a model for acute kidney injury (AKI) used by four groups of the Research Unit. Capsaicin significantly increases I/Rdependent increase of TRPV1 mRNA expression in the specific kidney regions. Here we evaluate the role of TRPV1 in I/R-dependent AKI, its regulation by vascular factors with major focus at 20-HETE and other CYP-eicosanoids. To this end we test (i) drugs that specifically target TRPV1 channels, (ii) knockout and transgenic mice with genetically modified TRPV1 channel expression and (iii) drugs that specifically target the synthesis and action of 20-HETE or epoxyeicosanoic acids (EETs). As endpoints we analyze I/R-induced expression and function of TRPV1 channels, renal dysfunction and tubular injury.

瞬时受体电位香草酸1型（TRPV 1）通道是一种配体门控的非选择性阳离子通道，可被内源性物质20-羟基二十碳四烯酸（20-HETE）和外源性物质辣椒素（辣椒辣素）激活。我们假设TRPV 1通道通过调节肾血流在缺血性阿基中起关键作用。TRPV 1通道及其天然激活剂20-HETE也可能有助于血管和肾小管修复过程，从而允许在缺血/再灌注（I/R）诱导的损伤后恢复肾功能。最近的文献和自己的初步结果确实表明，TRPV 1通道和20-HETE在肾I/R损伤（研究单位的四个小组使用的急性肾损伤（阿基）模型）的血管张力调节中发挥重要作用。辣椒素显著增加I/R依赖的TRPV 1 mRNA在特定肾脏区域表达的增加。在这里，我们评估TRPV 1在I/R依赖性阿基中的作用，其受血管因子的调节，主要集中在20-HETE和其他CYP-类花生酸。为此，我们测试了（i）特异性靶向TRPV 1通道的药物，（ii）具有遗传修饰的TRPV 1通道表达的敲除和转基因小鼠，以及（iii）特异性靶向20-HETE或环氧二十烷酸（ESTO）的合成和作用的药物。作为终点，我们分析了I/R诱导的TRPV 1通道的表达和功能、肾功能不全和肾小管损伤。