Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+-HCO3- transport
Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+-HCO3- transport
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DOI：
10.1681/asn.2007030289
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发表时间：
2008-02-01
影响因子：
13.6
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Li, Yuehong;Yamada, Hideomi;Fujita, Toshiro
血管紧张素II（Ang II）对肾脏近端转运的调节是双相的：低浓度（皮摩尔至纳摩尔）刺激重吸收，但高浓度（纳摩尔至微摩尔）抑制重吸收。传统上，刺激作用归因于蛋白激酶C的激活和/或细胞内cAMP的减少，而抑制作用归因于磷脂酶A（2）（PLA（2））的激活和随后花生四烯酸的释放。负责这些作用的Ang II受体亚型和所涉及的细胞内信号传导途径尚未完全了解。我们从野生型、Ang II 1A型受体（AT（1A））缺陷型和IVA型胞质磷脂酶A（2）（cPLA（2）α）缺陷型小鼠中分离近端小管，并比较它们对Ang II的反应。在野生型小鼠中，我们发现Ang II对Na+-HCO 3-协同转运体活性的刺激和抑制作用都是AT（1）介导的，但ERK激活仅在前者中起作用。在AT（1A）缺陷小鼠中也观察到Ang II的刺激作用，表明这是通过AT（1B）发生的。与此相反，Ang II的抑制作用似乎是由cPLA 2a激活介导的，因为当通过药理学手段或基因敲除废除cPLA 2a活性时，高浓度Ang II刺激Na+-HCO 3-共转运体活性。与这一观察结果相一致，我们发现cPLA（2）α/P450通路的激活抑制了ERK的激活。我们的结论是，Ang II通过AT（1）以浓度依赖性方式激活ERK和cPLA 2 α，ERK和cPLA（2）α活性之间的平衡决定了完整近端小管对Ang II的最终反应。
Regulation of renal proximal transport by angiotensin II (Ang II) is biphasic: low concentrations (picomolar to nanomolar) stimulate reabsorption, but higher concentrations (nanomolar to micromolar) inhibit reabsorption. Traditionally, the stimulatory effect has been attributed to activation of protein kinase C and/or a decrease in intracellular cAMP, whereas the inhibitory action has been attributed to the activation of phospholipase A(2) (PLA(2)) and the subsequent release of arachidonic acid. The Ang II receptor subtype responsible for these effects and the intracellular signaling pathways involved are not completely understood. We isolated proximal tubules from wild-type, Ang II type 1A receptor (AT(1A))-deficient, and group IVA cytosolic phospholipase A(2) (cPLA(2)alpha)- deficient mice, and compared their responses to Ang II. In wild-type mice, we found that the stimulatory and inhibitory effects of Ang II on Na+-HCO3- cotransporter activity are both AT(1)-mediated but that ERK activation only plays a role in the former. The stimulatory effect of Ang II was also observed in AT(1A)-deficient mice, suggesting that this occurs through AT(1B). In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA2a activation because high-concentration Ang II stimulated Na+-HCO3- cotransporter activity when cPLA2a activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA(2)alpha/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA2 alpha in a concentration-dependent manner via AT(1), and that the balance between ERK and cPLA(2)alpha activities determines the ultimate response to Ang II in intact proximal tubules.