Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561, USA.
Am J Physiol Renal Physiol. 2010 Mar;298(3):F683-91. doi: 10.1152/ajprenal.00503.2009. Epub 2009 Dec 30.
Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor.
血管紧张素 1 型（AT1）受体阻滞剂（ARB）可改善慢性肾脏病的进展。这种保护作用仅仅是由于阻断 AT1，还是由于将血管紧张素 II 从 AT1 转移到可用的 AT2 受体，从而潜在增强 AT2 受体的作用尚不清楚。因此，我们研究了 AT2 受体在 ARB 诱导的慢性肾脏病治疗中的作用。成年大鼠接受 5/6 肾切除术。8 周后通过肾活检评估肾小球硬化，将大鼠分为具有等效肾小球硬化的四组：无进一步治疗、ARB、AT2 受体拮抗剂或联合治疗。肾切除后 12 周，所有治疗组的收缩压均降低，但仅 ARB 组的蛋白尿减少。与 ARB 相比，AT2 受体拮抗剂组的肾小球硬化显著增加。ARB 组肾皮质胶原含量减少，但未治疗的 5/6 肾切除组、AT2 受体拮抗剂组和联合组的胶原含量增加。未治疗的 5/6 肾切除组和 AT2 受体拮抗剂组的肾小球细胞增殖均增加，而与 ARB 相比，磷酸化 Erk2 增加。与 ARB 降低相反，AT2 受体拮抗剂在 12 周时增加了纤溶酶原激活物抑制剂-1mRNA 和蛋白的表达。足细胞损伤是肾小球硬化的一个关键组成部分。因此，我们评估了 AT1 与 AT2 阻断对足细胞的影响及其与纤溶酶原激活物抑制剂-1 的相互作用。与野生型足细胞相比，培养的纤溶酶原激活物抑制剂-1 敲除细胞对血管紧张素 II 的反应是增加胶原，ARB 完全阻断了这种反应，而 AT2 受体拮抗剂的作用较小。我们的结论是，ARB 对肾小球损伤的有益作用不仅归因于阻断 AT1 受体，而且还归因于通过 AT2 受体转导增加血管紧张素的作用。
