Department of Medicine, the Neuroscience Program, Michigan State University, East Lansing, Michigan 48824, USA.
Endocrinology. 2011 Oct;152(10):3811-9. doi: 10.1210/en.2011-0141. Epub 2011 Aug 16.
We test the hypothesis that 12-hydroperoxyeicosatetraenoic acid (12(s)-HPETE) and 12-hydroxyeicosatetraenoic acid (12-HETE) perfused into the renal pelvis increase afferent renal nerve activity (ARNA) and suppress renin release in rats fed a low-salt (LS) diet via activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in renal sensory nerves. 12(s)-HPETE or 12-HETE given into the left renal pelvis dose-dependently increased ARNA, which was abolished by AMG9810, a selective TRPV1 antagonist, or by RP67580, a selective neurokinin 1 receptor antagonist, in normal salt or LS-treated rats. 12(s)-HPETE, 12-HETE, or substance P perfused into the left renal pelvis suppressed plasma angiotensin I (Ang I) levels in LS rats, which was abolished by AMG9810 or attenuated by ipsilateral renal denervation (RD). 12(s)-HPETE or 12-HETE increased release of substance P and calcitonin gene-related peptide from the ipsilateral kidney, which was abolished by AMG9810 but not RP67580, RD, or RP67580 plus RD. Immunofluorescence staining showed that TRPV1-positive nerve fibers located in the renal cortex, medulla, and pelvis, and that the sympathetic nerve marker, neuropeptide Y, but not neurokinin 1 receptors expressed in the juxtaglomerular region colocalized with renin. Thus, our data show that 12(s)-HPETE and 12-HETE enhance ARNA and substance P/calcitonin gene-related peptide release but suppress renin activity in LS rats, and these effects are abolished when TRPV1 is blocked. These results indicate that TRPV1 mediates 12(s)-HPETE and 12-HETE action in the kidney in such a way that dysfunction in TRPV1 may lead to disintegrated regulation of renin and renal function.
我们检验了这样一个假设，即 12-羟过氧二十碳四烯酸（12(s)-HPETE）和 12-羟二十碳四烯酸（12-HETE）灌注到肾盂中会通过激活肾感觉神经中表达的瞬时受体电位香草酸型 1（TRPV1），增加低盐（LS）饮食喂养的大鼠的传入肾神经活动（ARNA）并抑制肾素释放。在正常盐或 LS 处理的大鼠中，给予左肾盂的 12(s)-HPETE 或 12-HETE 剂量依赖性地增加 ARNA，这种增加被 TRPV1 选择性拮抗剂 AMG9810 或神经激肽 1 受体选择性拮抗剂 RP67580 所消除。12(s)-HPETE、12-HETE 或 P 物质灌注到左肾盂会抑制 LS 大鼠的血浆血管紧张素 I（Ang I）水平，这种抑制被 AMG9810 消除或被同侧肾去神经支配（RD）减弱。12(s)-HPETE 或 12-HETE 增加同侧肾脏释放 P 物质和降钙素基因相关肽，这种增加被 AMG9810 消除，但不受 RP67580、RD 或 RP67580 加 RD 的影响。免疫荧光染色显示，TRPV1 阳性神经纤维位于肾皮质、髓质和肾盂，而位于肾小球旁器的交感神经标记物神经肽 Y，但不是神经激肽 1 受体与肾素共定位。因此，我们的数据表明，12(s)-HPETE 和 12-HETE 增强 LS 大鼠的 ARNA 和 P 物质/降钙素基因相关肽释放，但抑制肾素活性，当 TRPV1 被阻断时，这些作用被消除。这些结果表明，TRPV1 介导了 12(s)-HPETE 和 12-HETE 在肾脏中的作用，TRPV1 功能障碍可能导致肾素和肾功能的调节失调。
