Benndorf Ralf A, Krebs Christian, Hirsch-Hoffmann Birgit, Schwedhelm Edzard, Cieslar Gabriele, Schmidt-Haupt Robin, Steinmetz Oliver M, Meyer-Schwesinger Catherine, Thaiss Friedrich, Haddad Munif, Fehr Susanne, Heilmann Andreas, Helmchen Udo, Hein Lutz, Ehmke Heimo, Stahl Rolf A, Böger Rainer H, Wenzel Ulrich O
Clinical Pharmacology Unit, Institute of Experimental and Clinical Toxicology and Pharmacology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Kidney Int. 2009 May;75(10):1039-49. doi: 10.1038/ki.2009.2. Epub 2009 Feb 11.
Angiotensin II (Ang II) activates at least two receptors, AT1 and AT2, with the majority of its effects-such as vasoconstriction, inflammation, and matrix deposition-mediated by the AT1 receptor. It is thought that the AT2 receptor counteracts these processes; however, recent studies have found proinflammatory and hypertrophic effects of this receptor subtype. To identify the physiological roles of the AT2 receptor in chronic kidney disease, we performed renal ablation in AT2 receptor knockout and wild-type mice. Renal injury caused a greater impairment of renal function, glomerular injury, albuminuria, and mortality in the knockout mice than in the wild-type mice. There was increased fibronectin expression and inflammation in the knockout mice, as shown by augmented monocyte/macrophage infiltration and higher chemokine monocyte chemotactic protein-1 (MCP-1) and RANTES expression in the remnant kidney. The higher mortality and renal morbidity of the knockout mice was not due to differences in systemic blood pressure, glomerular volume, AT1 receptor, renin, or endothelial nitric oxide synthase expression. Whether activation of the AT2 receptor will have therapeutic benefit in chronic kidney disease will require further study.
血管紧张素II（Ang II）激活至少两种受体，即AT1和AT2，其大部分作用（如血管收缩、炎症和基质沉积）由AT1受体介导。人们认为AT2受体可抵消这些过程；然而，最近的研究发现该受体亚型具有促炎和肥大作用。为了确定AT2受体在慢性肾脏病中的生理作用，我们在AT2受体基因敲除小鼠和野生型小鼠中进行了肾切除。与野生型小鼠相比，肾损伤在基因敲除小鼠中导致更严重的肾功能损害、肾小球损伤、蛋白尿和死亡率。基因敲除小鼠中纤连蛋白表达增加且有炎症，残余肾中单核细胞/巨噬细胞浸润增加以及趋化因子单核细胞趋化蛋白-1（MCP-1）和调节激活正常T细胞表达和分泌因子（RANTES）表达升高即表明了这一点。基因敲除小鼠较高的死亡率和肾脏发病率并非由于全身血压、肾小球体积、AT1受体、肾素或内皮型一氧化氮合酶表达的差异所致。激活AT2受体在慢性肾脏病中是否具有治疗益处尚需进一步研究。
