Department of Biochemistry and Molecular Biology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
Hypertension. 2010 May;55(5):1246-53. doi: 10.1161/HYPERTENSIONAHA.110.150540. Epub 2010 Mar 29.
Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy for which the pathophysiology remains largely undefined. Recently, a circulating maternal autoantibody, the angiotensin II type I (AT(1)) receptor agonistic autoantibody (AA), has emerged as a contributor to disease features. Increased circulating maternal tumor necrosis factor alpha (TNF-alpha) is also associated with the disease; however, it is unknown whether this factor directly contributes to preeclamptic symptoms. Here we report that this autoantibody increases the proinflammatory cytokine TNF-alpha in the circulation of AT(1)-AA-injected pregnant mice but not in nonpregnant mice. Coinjection of AT(1)-AA with a TNF-alpha neutralizing antibody reduced cytokine availability in AT(1)-AA-injected pregnant mice. Moreover, TNF-alpha blockade in AT(1)-AA-injected pregnant mice significantly attenuated the key features of preeclampsia. Autoantibody-induced hypertension was reduced from 131+/-4 to 110+/-4 mm Hg, and proteinuria was reduced from 212+/-25 to 155+/-23 microg of albumin per milligram of creatinine (both P<0.05). Injection of AT(1)-AA increased the serum levels of circulating soluble fms-like tyrosine kinase 1 and soluble endoglin (34.1+/-5.1, 2.4+/-0.3 ng/mL, respectively) and coinjection with the TNF-alpha blocker significantly reduced their levels (21.7+/-3.4 and 1.2+/-0.4 ng/mL, respectively). Renal damage and placental abnormalities were also decreased by TNF-alpha blockade. Lastly, the elevated circulating TNF-alpha in preeclamptic patients is significantly correlated with the AT(1)-AA bioactivity in our patient cohort. Similarly, the autoantibody, through AT(1) receptor-mediated TNF-alpha induction, contributed to increased soluble fms-like tyrosine kinase 1, soluble endoglin secretion, and increased apoptosis in cultured human villous explants. Overall, AT(1)-AA is a novel candidate that induces TNF-alpha, a cytokine that may play an important pathogenic role in preeclampsia.
子痫前期是一种常见的危及生命的妊娠高血压疾病，其病理生理学仍很大程度上未得到明确。最近，一种循环的母体自身抗体，血管紧张素 II 型 1（AT（1））受体激动性自身抗体（AA），已成为疾病特征的一个贡献因素。循环母体内肿瘤坏死因子 alpha（TNF-alpha）的增加也与该疾病有关；然而，尚不清楚该因子是否直接导致子痫前期症状。在这里，我们报告称，这种自身抗体增加了 AT（1）-AA 注射怀孕小鼠但不是非怀孕小鼠的循环中促炎细胞因子 TNF-alpha。AT（1）-AA 与 TNF-alpha 中和抗体共注射可减少 AT（1）-AA 注射怀孕小鼠中细胞因子的可用性。此外，在 AT（1）-AA 注射怀孕小鼠中阻断 TNF-alpha 可显著减轻子痫前期的关键特征。自身抗体诱导的高血压从 131+/-4 降至 110+/-4 mmHg，蛋白尿从 212+/-25 降至 155+/-23 microg 白蛋白/毫克肌酐（均 P<0.05）。注射 AT（1）-AA 增加了循环可溶性 fms 样酪氨酸激酶 1 和可溶性内皮素的血清水平（分别为 34.1+/-5.1、2.4+/-0.3 ng/mL），而与 TNF-alpha 阻滞剂共注射则显著降低了它们的水平（分别为 21.7+/-3.4 和 1.2+/-0.4 ng/mL）。TNF-alpha 阻断也减少了肾脏损伤和胎盘异常。最后，子痫前期患者循环中升高的 TNF-alpha 与我们患者队列中的 AT（1）-AA 生物活性显著相关。同样，该自身抗体通过 AT（1）受体介导的 TNF-alpha 诱导，导致培养的人绒毛膜绒毛外植体中可溶性 fms 样酪氨酸激酶 1、可溶性内皮素分泌和细胞凋亡增加。总体而言，AT（1）-AA 是一种新型候选物，可诱导 TNF-alpha，该细胞因子可能在子痫前期中发挥重要的致病作用。
