Esteban Vanesa, Ruperez Mónica, Vita Juan Rodriguez, López Elsa Sanchez, Mezzano Sergio, Plaza Juan José, Egido Jesús, Ruiz-Ortega Marta
Laboratory of Vascular and Renal Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Kidney Int Suppl. 2003 Oct(86):S33-8. doi: 10.1046/j.1523-1755.64.s86.7.x.
Angiotensin II (Ang II) is a cytokine that participates in the inflammatory response. The nuclear factor kappa B (NFkappaB) is involved in the regulation of many immune and inflammatory factors. Different works have shown that both angiotensin II receptor type 1 (AT1) and type 2 (AT2) receptors are involved in the NFkappaB pathway; however, some aspects remain mysterious. AT1 antagonists increased plasma Ang II levels that could bind to AT2, so understanding the clinical importance of AT2 stimulation or inhibition is an interesting unresolved point.
Experiments were done in wild-type (WT) and AT1a receptor knockout mice that received subcutaneous Ang II infusions (1000 ng/kg/min) for 3 days. Specific blockers of AT1 (losartan 10 mg/kg/day) and AT2 (PD123319 30 mg/kg/day) receptors were administered 1 day before and during Ang II infusion. NFkappaB activity was examined by electrophoretic mobility assay and inflammatory (monocyte/macrophage) cell infiltration by immunohistochemistry
In WT mice, Ang II infusion caused renal NFkappaB activation that was partially diminished by either AT1 or AT2 antagonists. In AT1 knockout mice, Ang II also activated renal NFkappaB, which was only blocked by the AT2 antagonist. Both Ang II-infused WT and AT1 knockout mice showed inflammatory infiltration in tubulointerstitial areas that were suppressed by the AT2, but not AT1, antagonist. Combined therapy of both AT1 and AT2 antagonists blocked renal NFkappaB activation and inflammatory cell infiltration, both in WT and in AT1 knockout mice.
Ang II, via AT1 and AT2 stimulation, leads to NFkappaB activation that was only blocked by combined therapy with both antagonists. The participation of AT2 receptors in the recruitment of inflammatory cells underscores the need of future studies that evaluate the clinical usefulness of this strategy.
血管紧张素II（Ang II）是一种参与炎症反应的细胞因子。核因子κB（NFκB）参与多种免疫和炎症因子的调节。不同的研究表明，1型血管紧张素II受体（AT1）和2型血管紧张素II受体（AT2）均参与NFκB信号通路；然而，一些方面仍不清楚。AT1拮抗剂会增加可与AT2结合的血浆Ang II水平，因此了解AT2激动或抑制的临床重要性是一个有趣的未解决问题。
对野生型（WT）和AT1a受体敲除小鼠进行实验，这些小鼠皮下输注Ang II（1000 ng/kg/分钟），持续3天。在输注Ang II前1天及输注期间给予AT1（氯沙坦10 mg/kg/天）和AT2（PD123319 30 mg/kg/天）受体的特异性阻滞剂。通过电泳迁移率测定法检测NFκB活性，通过免疫组织化学检测炎症（单核细胞/巨噬细胞）细胞浸润情况。
在WT小鼠中，输注Ang II导致肾脏NFκB激活，AT1或AT2拮抗剂均可部分减轻这种激活。在AT1敲除小鼠中，Ang II也激活了肾脏NFκB，这仅被AT2拮抗剂阻断。输注Ang II的WT和AT1敲除小鼠在肾小管间质区域均出现炎症浸润，AT2拮抗剂可抑制这种浸润，但AT1拮抗剂不能。AT1和AT2拮抗剂联合治疗可阻断WT和AT1敲除小鼠的肾脏NFκB激活和炎症细胞浸润。
Ang II通过刺激AT1和AT2导致NFκB激活，只有两种拮抗剂联合治疗才能阻断这种激活。AT2受体在炎症细胞募集中的作用突出了未来评估该策略临床实用性研究的必要性。
