Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Berlin, Germany.
Transplantation. 2012 Jul 15;94(1):8-13. doi: 10.1097/TP.0b013e3182529bb7.
We previously described angiotensin II type 1 receptor-activating antibodies (AT1R-Abs) in renal transplant recipients with vascular rejection and malignant hypertension. In this study, we tested the hypothesis that AT1R-Abs can cause renal artery contraction by AT1R activation with renal ischemia representing a key permissive factor and therefore contribute to renal pathologic condition.
Isolated renal and mesenteric arteries from Lewis rats were incubated with purified AT1R-Abs from patients with human leukocyte antigen antibody-negative vascular rejection. Vascular contraction was measured using small vessel myography. The measurements were repeated with renal arteries derived from native kidneys subjected to ischemia-reperfusion or after transplantation in a low-responder Fischer 344-to-Lewis rat kidney-transplantation model.
AT1R-Abs acted in a vascular bed-specific manner and caused small contractions only in native rat renal arteries but not in mesenteric arteries. AT1R-Abs did not alter the vascular reactivity to phenylephrine, angiotensin II, or acetylcholine in native renal arteries. In contrast, AT1R-Abs caused a pronounced (>10-fold) contraction of renal arteries after ischemia and after allogeneic transplantation. Pretreatment with pharmacologic AT1R blocker only partially inhibited the AT1R-Abs-induced contraction, which was almost completely abolished by neutralizing peptides targeting epitopes of AT1R-Abs on the second loop of AT1R.
These data demonstrate that AT1R-Abs can induce renal vascular contraction under predisposing conditions such as in ischemic or transplanted kidneys. Neutralizing antibodies against specific epitopes in the AT1R can ameliorate this contraction.
我们之前在发生血管性排斥反应和恶性高血压的肾移植受者中描述了血管紧张素 II 型 1 型受体激活抗体（AT1R-Abs）。在这项研究中，我们检验了这样一个假设，即 AT1R-Abs 可通过 AT1R 激活引起肾动脉收缩，而肾缺血是关键的许可因素，因此导致肾脏病理状况。
用来自人类白细胞抗原抗体阴性血管排斥反应患者的纯化 AT1R-Abs 孵育来自 Lewis 大鼠的分离的肾和肠系膜动脉。使用小血管肌动描记术测量血管收缩。对来自未受影响的肾脏的肾动脉进行重复测量，这些肾动脉经历缺血再灌注，或在低反应性 Fischer 344 至 Lewis 大鼠肾移植模型中进行移植后。
AT1R-Abs 以血管床特异性的方式起作用，仅在原代大鼠肾动脉中引起小收缩，而不在肠系膜动脉中引起收缩。AT1R-Abs 不会改变原代肾动脉对苯肾上腺素、血管紧张素 II 或乙酰胆碱的血管反应性。相比之下，AT1R-Abs 在缺血后和同种异体移植后引起肾动脉明显（>10 倍）收缩。用药理学 AT1R 阻滞剂预处理仅部分抑制了 AT1R-Abs 诱导的收缩，而用针对 AT1R-Abs 在 AT1R 第二环上的表位的中和肽则几乎完全消除了这种收缩。
这些数据表明，AT1R-Abs 可在易患条件下（如在缺血或移植肾脏中）诱导肾血管收缩。针对 AT1R 中特定表位的中和抗体可改善这种收缩。
