Wolf Gunter, Bohlender Jürgen, Bondeva Tzvetanka, Roger Thierry, Thaiss Friedrich, Wenzel Ulrich O
Klinik für Innere Medizin III, University of Jena, Germany, and Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
J Am Soc Nephrol. 2006 Jun;17(6):1585-93. doi: 10.1681/ASN.2005070699. Epub 2006 May 4.
Angiotensin II (AngII) mediates proinflammatory properties by activating NF-kappaB transcription factor nuclear translocation and inducing the expression of chemokines. For examination of whether AngII modulates the expression of Toll-like receptor 4 (TLR4), a key element of the innate immune system that senses LPS, mouse mesangial cells (MMC) were treated with AngII. AngII upregulated TLR4 mRNA and protein in MMC, and this effect was mediated through AngII type 1 receptors. Reporter gene experiments indicate that an activating protein-1 (AP-1) as well as an E-26 specific sequence (Ets) binding site in the TLR4 promoter are responsible for the AngII-stimulated transcriptional activity of the TLR4 gene. Preincubation of MMC with AngII enhanced LPS-induced NF-kappaB activation and chemokine expression. Immunohistochemical analyses revealed that double-transgenic rats that overexpressed human renin and angiotensinogen expressed higher levels of glomerular TLR4 compared with normal Sprague-Dawley rats. In vivo, infusion with AngII but not with norepinephrine into rats for 7 d also enhanced glomerular NF-kappaB activation after systemic application of LPS, suggesting that the effects are independent of concomitantly induced hypertension. Together, these observations suggest that AngII leads to an activation of the innate immune system by a novel mechanism involving the upregulation of TLR4. Our data contribute to a better understanding of how exogenous infections may trigger renal autoimmune processes, particularly in pathophysiologic situations with high renal AngII concentrations. Because TLR4 binds endogenous ligands (e.g., extracellular matrix components) in addition to microbial products, AngII-mediated upregulation of TLR4 also could be relevant for the development of inflammation in many noninfectious renal diseases.
血管紧张素II（AngII）通过激活核因子κB转录因子的核转位并诱导趋化因子的表达来介导促炎特性。为了检测AngII是否调节Toll样受体4（TLR4）的表达（TLR4是感知脂多糖的固有免疫系统的关键元件），用AngII处理小鼠系膜细胞（MMC）。AngII上调了MMC中TLR4的mRNA和蛋白水平，且这种作用是通过1型AngII受体介导的。报告基因实验表明，TLR4启动子中的激活蛋白-1（AP-1）以及E-26特异性序列（Ets）结合位点负责AngII刺激的TLR4基因转录活性。MMC与AngII预孵育可增强脂多糖诱导的核因子κB激活和趋化因子表达。免疫组织化学分析显示，与正常的斯普拉格-道利大鼠相比，过表达人肾素和血管紧张素原的双转基因大鼠肾小球TLR4表达水平更高。在体内，给大鼠输注AngII而非去甲肾上腺素7天，在全身应用脂多糖后也增强了肾小球核因子κB的激活，这表明这些作用独立于伴随诱导的高血压。总之，这些观察结果表明，AngII通过一种涉及TLR4上调的新机制导致固有免疫系统的激活。我们的数据有助于更好地理解外源性感染如何引发肾脏自身免疫过程，特别是在肾脏AngII浓度高的病理生理情况下。因为TLR4除了结合微生物产物外还结合内源性配体（如细胞外基质成分），AngII介导的TLR4上调也可能与许多非感染性肾脏疾病的炎症发展有关。
