Arachidonic Acid Metabolites Inhibit the Stimulatory Effect of Angiotensin II in Renal Proximal Tubules
Arachidonic Acid Metabolites Inhibit the Stimulatory Effect of Angiotensin II in Renal Proximal Tubules
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DOI：
10.1291/hypres.31.2155
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发表时间：
2008-12
影响因子：
5.4
通讯作者：
Yuehong Li;Hideomi Yamada;Y. Kita;Masashi Suzuki;Y. Endo;S. Horita;O. Yamazaki;Takao Shimizu;G. Seki;T. Fujita
中科院分区：
文献类型：
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作者：
Yuehong Li;Hideomi Yamada;Y. Kita;Masashi Suzuki;Y. Endo;S. Horita;O. Yamazaki;Takao Shimizu;G. Seki;T. Fujita
血管紧张素II（Ang II）通过Ang II 1型受体（AT 1）以双相方式调节肾脏近端转运。而细胞外信号调节激酶（ERK）激活介导的刺激作用，胞浆磷脂酶A2（cPLA2）介导的抑制作用独立于ERK。在这项研究中，我们测试的假设，cPLA2/P450环氧酶途径可能会抑制血管紧张素II介导的ERK激活。在存在花生四烯酸或5，6-环氧二十碳三烯酸（EET）的情况下，Ang II不能刺激从野生型、AT1A缺陷型和cPLA2-α缺陷型小鼠分离的肾近端小管中的Na-HCO3协同转运体活性。此外，在花生四烯酸或5，6-EET存在下，Ang II未能诱导显著的ERK磷酸化。花生四烯酸或5，6-EET也抑制了Ang II对近端小管净碳酸氢盐吸收的刺激作用，而不改变细胞Ca 2+浓度。提示cPLA2-α/P450/EET信号通路通过抑制ERK的激活而阻断Ang Ⅱ的刺激作用。因此，cPLA2-α/P450/EET通路可能作为一种独特的负反馈机制来减弱肾近端小管中过度的Ang II活性，其中发现了极高浓度的Ang II。
Angiotensin II (Ang II) regulates renal proximal transport in a biphasic way via Ang II type 1 receptor (AT1). Whereas extracellular signal-regulated kinase (ERK) activation mediates the stimulatory effect, cytosolic phospholipase A2 (cPLA2) mediates the inhibitory effect independently of ERK. In this study, we tested the hypothesis that the cPLA2/P450 epoxygenase pathway might work to suppress the Ang II-mediated ERK activation. In the presence of arachidonic acid or 5,6-epoxyeicosatrienoic acid (EET), Ang II failed to stimulate the Na-HCO3 cotransporter activity in renal proximal tubules isolated from wild-type, AT1A-deficient, and cPLA2-α–deficient mice. In addition, Ang II failed to induce a significant ERK phosphorylation in the presence of arachidonic acid or 5,6-EET. Arachidonic acid or 5,6-EET also suppressed the stimulatory effect of Ang II on net proximal tubule bicarbonate absorption without changing cell Ca2+ concentrations. These results indicate that the cPLA2-α/P450/EET pathway blocks the stimulatory effect of Ang II by suppressing the ERK activation. Thus, the cPLA2-α/P450/EET pathway may operate as a unique negative feedback mechanism to attenuate excessive Ang II activity in the renal proximal tubules, where extremely high concentrations of Ang II are found.