Ruiz-Ortega M, Lorenzo O, Rupérez M, Blanco J, Egido J
Laboratory of Vascular and Renal Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Am J Pathol. 2001 May;158(5):1743-56. doi: 10.1016/s0002-9440(10)64130-2.
Recent studies have pointed out the implication of angiotensin II (Ang II) in various pathological settings. However, the molecular mechanisms and the AngII receptor (AT) subtypes involved are not fully identified. We investigated whether AngII elicited the in vivo activation of nuclear transcription factors that play important roles in the pathogenesis of renal and vascular injury. Systemic infusion of Ang II into normal rats increased renal nuclear factor (NF)-kappaB and AP-1 binding activity that was associated with inflammatory cell infiltration and tubular damage. Interestingly, infiltrating cells presented activated NF-kappaB complexes, suggesting the involvement of AngII in inflammatory cell activation. When rats were treated with AT(1) or AT(2) receptor antagonists different responses were observed. The AT(1) antagonist diminished NF-kappaB activity in glomerular and tubular cells and abolished AP-1 in renal cells, improved tubular damage and normalized the arterial blood pressure. The AT(2) antagonist diminished mononuclear cell infiltration and NF-kappaB activity in glomerular and inflammatory cells, without any effect on AP-1 and blood pressure. These data suggest that AT(1) mainly mediates tubular injury via AP-1/NF-kappaB, whereas AT(2) receptor participates in the inflammatory cell infiltration in the kidney by NF-kappaB. Our results provide novel information on AngII receptor signaling and support the recent view of Ang II as a proinflammatory modulator.
近期研究指出血管紧张素II（Ang II）在多种病理情况下的作用。然而，其涉及的分子机制以及AngII受体（AT）亚型尚未完全明确。我们研究了AngII是否能在体内激活在肾和血管损伤发病机制中起重要作用的核转录因子。向正常大鼠全身输注Ang II可增加肾细胞核因子（NF）-κB和AP-1的结合活性，这与炎症细胞浸润和肾小管损伤相关。有趣的是，浸润细胞呈现出活化的NF-κB复合物，提示AngII参与炎症细胞激活。当用AT(1)或AT(2)受体拮抗剂处理大鼠时，观察到了不同的反应。AT(1)拮抗剂降低了肾小球和肾小管细胞中的NF-κB活性，并消除了肾细胞中的AP-1，改善了肾小管损伤并使动脉血压恢复正常。AT(2)拮抗剂减少了单核细胞浸润以及肾小球和炎症细胞中的NF-κB活性，对AP-1和血压无任何影响。这些数据表明，AT(1)主要通过AP-1/NF-κB介导肾小管损伤，而AT(2)受体通过NF-κB参与肾脏中的炎症细胞浸润。我们的结果提供了关于AngII受体信号传导的新信息，并支持了近期将Ang II视为促炎调节剂的观点。
