Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 Xitoutiao, You An Men Street, Beijing, 100069, China.
Beijing Key Laboratory of Cardiovascular Diseases and Related Metabolic Dysfunction, Capital Medical University, Beijing, China.
Immunol Res. 2018 Feb;66(1):44-51. doi: 10.1007/s12026-017-8963-6.
Preeclamptic women are reported to have inadequate plasma volume expansion coupled with a suppressed secretion of aldosterone; however, the specific mechanism of preeclampsia remains unclear. We demonstrated that the presence of long-term angiotensin II type 1 receptor autoantibody (AT1-AA) reduces aldosterone production by triggering a Ca overload in H295R cells. AT1-AA was discovered in preeclamptic women and reported to activate ATR, and consequently elevate intracellular Ca. We found that AT1-AA significantly prolonged the time of intracellular Ca elevation. Besides promoting aldosterone production as a second messenger, Ca overload shows a cytotoxic effect. Our data reveals that long-term presence of AT1-AA triggered a Ca overload and consequent impairment of aldosterone production, which could be prevented by a PKC inhibitor, Gö 6983, or a calcium channel inhibitor, nifedipine. These findings have clinical significance because ATR blockers are not recommended for treatment of preeclampsia due to their potential harm to the fetus. Our findings also emphasize a potential clinical benefit of immunoadsorption or neutralization of AT1-AA in preeclamptic women.
据报道，子痫前期患者的血浆容量扩张不足，同时醛固酮分泌受到抑制；然而，子痫前期的确切机制仍不清楚。我们证明，长期存在的血管紧张素 II 型 1 型受体自身抗体（AT1-AA）通过在 H295R 细胞中引发钙超载来减少醛固酮的产生。AT1-AA 存在于子痫前期妇女中，并被报道可激活 ATR，从而升高细胞内钙。我们发现 AT1-AA 显著延长了细胞内钙升高的时间。除了作为第二信使促进醛固酮的产生外，钙超载还表现出细胞毒性作用。我们的数据表明，长期存在的 AT1-AA 引发了钙超载，随后醛固酮的产生受到损害，而 PKC 抑制剂 Gö 6983 或钙通道抑制剂硝苯地平可预防这种损害。这些发现具有临床意义，因为 ATR 阻断剂不推荐用于子痫前期的治疗，因为它们可能对胎儿造成伤害。我们的研究结果还强调了在子痫前期妇女中免疫吸附或中和 AT1-AA 的潜在临床益处。
