Xiao Ling, Liu Hong-Wei, Di Hong, Chen Li-Xin, Zhou Qing, Yu Xin, Jing Haiyan, Tang Shuhai
Department of Physiology, Shandong University School of Medicine, Jinan, China.
Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, China.
Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):207-212. doi: 10.1016/j.bbrc.2017.10.052. Epub 2017 Oct 12.
A growing literature has demonstrated that the renin-angiotensin system (RAS) involves in gut function. Angiotensin II (AngII) stimulates Cl secretion in intestine epithelial cells. However, the underlying signal pathway remains unexplored. Here, we explored that serosal application of Ang II (5 × 10 M) significantly increased the baseline Isc compared to the control group in rat ileum. Tetrodotoxin (TTX) failed to suppress Isc evoked by Ang II. However, the Ang II-evoked Isc was significantly suppressed by the ATR antagonist losartan instead of ATR antagonist PD123319. Of interest, both cyclooxygenase (COX)-1 inhibitor SC560 and COX-2 specific inhibitor ns398 blocked the Ang II-evoked Isc. Preincubation of submucosa/mucosa preparations with Ang II for 10 min significantly increased PGE2 production, which was abolished by either COX-1 or COX-2 inhibitor. In addition, the Ang II-induced PGE2 release was also attenuated by ATR receptor antagonist rather than selective ATR receptor antagonist. Furthermore, preincubation of tissues for 15 min with forskolin, a cAMP activator, markedly blocked the Isc evoked by AngII, while intracellular Ca pump inhibitor thapsigargin, L-type Ca channel blocker nicadipine or the epithelial Na channel blocker amiloride didn't show such function. These results suggest that Ang II evokes cAMP-activated intestinal anion secretion by stimulating PGE2 release through activation of ATR1.
越来越多的文献表明，肾素-血管紧张素系统（RAS）参与肠道功能。血管紧张素II（AngII）刺激肠上皮细胞中的Cl分泌。然而，其潜在的信号通路仍未被探索。在此，我们发现，与对照组相比，在大鼠回肠中浆膜应用Ang II（5×10⁻⁶M）显著增加了基线短路电流（Isc）。河豚毒素（TTX）未能抑制Ang II诱发的Isc。然而，Ang II诱发的Isc被ATR拮抗剂氯沙坦显著抑制，而不是被ATR拮抗剂PD123319抑制。有趣的是，环氧化酶（COX）-1抑制剂SC560和COX-2特异性抑制剂ns398都阻断了Ang II诱发的Isc。用Ang II对黏膜下层/黏膜制剂进行预孵育10分钟可显著增加前列腺素E2（PGE2）的产生，这被COX-1或COX-2抑制剂所消除。此外，Ang II诱导的PGE2释放也被ATR受体拮抗剂而非选择性ATR受体拮抗剂所减弱。此外，用环磷腺苷（cAMP）激活剂福斯可林对组织进行15分钟的预孵育，可显著阻断AngII诱发的Isc，而细胞内钙泵抑制剂毒胡萝卜素、L型钙通道阻滞剂尼卡地平或上皮钠通道阻滞剂阿米洛利则没有这种作用。这些结果表明，Ang II通过激活ATR1刺激PGE2释放，从而诱发cAMP激活的肠道阴离子分泌。
