Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
J Hypertens. 2011 Oct;29(10):1919-29. doi: 10.1097/HJH.0b013e32834a5a46.
We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade.
Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-β, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-β, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed.
These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.
我们之前的研究表明，与血管紧张素 II 型 1 受体（AT1R）相互作用的分子 ATRAP 可促进 AT1R 内化，并减弱 AT1R 介导的病理性反应。在本研究中，我们研究了肾 ATRAP 表达的调节是否与盐诱导的高血压和肾脏损伤的发展有关，以及与 AT1R 阻断的有益作用有关。
Dahl Iwai 盐敏感型高血压大鼠和 Dahl Iwai 盐抵抗型大鼠分为六组，分别连续给予 Vehicle 或奥美沙坦 16 周，或从断奶到青春期（3-10 周）给予奥美沙坦短暂处理，然后给予高盐饮食 16 周。在 Dahl Iwai 盐敏感型大鼠中，连续给予奥美沙坦，甚至青春期前给予奥美沙坦，均可改善 15 周时的高血压。在 Vehicle 处理的 Dahl Iwai 盐敏感型大鼠中，肾 ATRAP 表达受到抑制，同时伴有肾氧化应激、炎症和纤维化相关标志物如 p22phox、TGF-β、纤连蛋白、单核细胞趋化蛋白-1 和 I 型胶原的上调。然而，青春期前和连续给予奥美沙坦可恢复受抑制的肾 ATRAP 表达，并抑制肾 p22phox、TGF-β、纤连蛋白、MCP-1 和 I 型胶原的激活。在 Dahl Iwai 盐抵抗型大鼠中，盐负荷并未观察到肾 ATRAP 表达的抑制或肾病理性反应的诱导。
这些结果表明，青春期前短暂阻断 AT1R 信号转导对 Dahl Iwai 盐敏感型大鼠的盐诱导性高血压和肾脏损伤具有长期的治疗作用，部分是通过持续增强肾 ATRAP 表达来实现的，提示 ATRAP 是盐诱导性高血压和肾脏损伤的一个新的分子靶点。
