AIM P-glycoprotein (Pgp/MDR1) plays a major role in intestinal homeostasis. Decrease in Pgp function and expression has been implicated in the pathogenesis of IBD. However, inhibitory mechanisms involved in the decrease of Pgp in inflammation are not fully understood. Angiotensin II (Ang II), a peptide hormone predominantly expressed in the epithelial cells of the crypt-villus junction of the intestine, has been shown to exert pro-inflammatory effects in the gut. It is increased in IBD patients and animals with experimental colitis. Whether Ang II directly influences Pgp is not known. METHODS Pgp activity was measured as verapamil-sensitive 3 H-digoxin flux. Pgp surface expression and exocytosis were measured by cell surface biotinylation studies. Signalling pathways were elucidated by Western blot analysis and pharmacological approaches. RESULTS Ang II (10 nM) significantly inhibited Pgp activity at 60 minutes. Ang II-mediated effects on Pgp function were receptor-mediated as the Ang II receptor 1 (ATR1) antagonist, losartan, blocked Pgp inhibition. Ang II effects on Pgp activity appeared to be mediated via PI3 kinase, p38 MAPK and Akt signalling. Ang II-mediated inhibition of Pgp activity was associated with a decrease in the surface membrane expression of Pgp protein via decreased exocytosis and was found to be dependent on the Akt pathway. Short-term treatment of Ang II (2 mg/kg b.wt., 2 hours) to mice also decreased the membrane expression of Pgp protein levels in ileum and colon. CONCLUSION Our findings provide novel insights into the role of Ang II and ATR1 in decreasing Pgp expression in intestinal inflammation.

中文翻译：

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血管紧张素II抑制肠上皮细胞中的P-糖蛋白。

AIM P糖蛋白（Pgp / MDR1）在肠道动态平衡中起主要作用。Pgp功能和表达的降低已被认为与IBD的发病机制有关。但是，尚未完全了解炎症中Pgp降低所涉及的抑制机制。血管紧张素II（Ang II）是一种主要在肠道隐窝-绒毛连接上皮细胞中表达的肽激素，已显示在肠道中具有促炎作用。在患有实验性结肠炎的IBD患者和动物中，它会增加。Ang II是否直接影响Pgp尚不清楚。方法以维拉帕米敏感的3 H-地高辛通量测定Pgp活性。通过细胞表面生物素化研究来测量Pgp表面表达和胞吐作用。通过蛋白质印迹分析和药理学方法阐明了信号通路。结果Ang II（10 nM）在60分钟时显着抑制Pgp活性。Ang II介导的对Pgp功能的作用是受体介导的，因为Ang II受体1（ATR1）拮抗剂洛沙坦阻断了Pgp的抑制作用。Ang II对Pgp活性的影响似乎是通过PI3激酶，p38 MAPK和Akt信号传导介导的。Ang II介导的对Pgp活性的抑制作用与通过减少胞吐作用减少Pgp蛋白的表面膜表达有关，并且被发现依赖于Akt途径。对小鼠短期治疗Ang II（2 mg / kg体重，2小时）也降低了回肠和结肠中Pgp蛋白水平的膜表达。结论我们的发现为Ang II和ATR1在降低肠道炎症中Pgp表达中的作用提供了新颖的见解。