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

瞬时受体电位香草酸1(TRPV1)通道是一种配体门控型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)激活。我们假设TRPV1通道通过调节肾血流在缺血性AKI中起关键作用。TRPV1通道和它们的天然激活剂20-HETE也可能参与血管和肾小管修复过程，使缺血/再灌注(I/R)诱导的损伤后肾功能恢复。最近的文献和自己的初步结果确实表明，TRPV1通道和20-HETE在肾I/R损伤的血管张力调节中发挥重要作用，这是一个研究单位的四个小组使用的急性肾损伤(AKI)模型。辣椒素显著增加缺血/再灌流依赖的肾脏特定区域TRPV1mRNA的表达。在这里，我们评估了TRPV1在依赖I/R的AKI中的作用，以及血管因素对其的调节，主要集中在20-HETE和其他CYP-二十烷基类化合物。为此，我们测试(I)专门针对TRPV1通道的药物，(Ii)表达转基因TRPV1通道的基因敲除和转基因小鼠，以及(Iii)专门针对20-HETE或环氧二十烷酸(EETs)的合成和作用的药物。作为终点，我们分析了I/R诱导的TRPV1通道的表达和功能、肾功能障碍和肾小管损伤。

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.