Obligatory Role for B Cells in the Development of Angiotensin II-Dependent Hypertension
Obligatory Role for B Cells in the Development of Angiotensin II-Dependent Hypertension
复制标题
DOI：
10.1161/hypertensionaha.115.05779
复制
发表时间：
2015-11-01
期刊：
影响因子：
8.3
通讯作者：
Drummond, Grant R.
中科院分区：
文献类型：
--
作者：
Chan, Christopher T.;Sobey, Christopher G.;Drummond, Grant R.
临床高血压与血清 IgG 抗体升高有关。然而，抗体是否是高血压的致病因素仍不清楚。我们研究了小鼠的高血压是否与 B 细胞激活和 IgG 产生有关，此外，B 细胞/IgG 缺乏是否可以提供针对高血压和血管重塑的保护作用。血管紧张素 II (Ang II) 输注（每天 0.7 毫克/千克；28 天）与 (1) 表达激活标记 CD86 的脾 B 细胞比例增加 25%，(2) 脾浆细胞数量增加 80%，(3) 循环 IgG 增加 500%，以及 (4) 主动脉外膜中 IgG 明显积累相关。在缺乏成熟 B 细胞的 B 细胞激活因子受体缺陷 (BAFF-R-/-) 小鼠中，没有证据表明 Ang II 诱导血清 IgG 增加。此外，相对于野生型（41 +/- 5 mm Hg）小鼠，BAFF-R-/-（30 +/- 4 mm Hg）小鼠对Ang II的高血压反应减弱，并且这种反应通过B细胞移植得以挽救。 BAFF-R-/- 小鼠的主动脉中 IgG 积累减少，这与主动脉巨噬细胞减少 80% 和转化生长因子表达减少 70% 相关。 BAFF-R-/- 小鼠也免受 Ang II 诱导的胶原沉积和主动脉硬化（通过脉搏波速度分析评估）。最后，与 BAFF-R 缺陷一样，用抗 CD20 抗体对 B 细胞进行药理学耗竭，可将 Ang II 诱导的高血压减弱约 35%。因此，这些研究表明 B 细胞/IgG 对于 Ang II 诱导的小鼠高血压和血管重塑的发生至关重要。因此，目前用于治疗自身免疫性疾病的 B 细胞靶向疗法可能有望成为未来高血压的治疗方法。
Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25% increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80% increase in splenic plasma cell numbers, (3) a 500% increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R-/-) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R-/- (30 +/- 4 mm Hg) relative to wild-type (41 +/- 5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R-/- mice displayed reduced IgG accumulation in the aorta, which was associated with 80% fewer aortic macrophages and a 70% reduction in transforming growth factor- expression. BAFF-R-/- mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by approximate to 35%. Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapiescurrently used for autoimmune diseasesmay hold promise as future treatments for hypertension.