Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats
Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats
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DOI：
10.1097/hjh.0b013e32834a5a46
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发表时间：
2011-10-01
影响因子：
4.9
通讯作者：
Umemura, Satoshi
中科院分区：
文献类型：
--
作者：
Dejima, Toru;Tamura, Kouichi;Umemura, Satoshi
目的研究血管紧张素Ⅱ 1型受体（AT 1 R）的相互作用分子ATRAP，ATRAP可促进AT 1 R的内化，并减弱AT 1 R介导的病理反应。在这项研究中，我们研究了肾脏ATRAP表达的调节是否与盐诱导的高血压和肾损伤的发展以及AT 1 R阻断的有益作用有关。方法和结果将Dahl Iwai盐敏感性高血压和Dahl Iwai盐抵抗大鼠分为6组，分别连续3至16周给予溶媒或奥美沙坦，或从断奶到青春期（3-10周）的短暂时间，从6 - 16周喂高盐饮食。在Dahl Iwai盐敏感大鼠中，不仅连续，而且青春期前奥美沙坦治疗在15周时改善了高血压。肾脏ATRAP的表达被抑制在车辆处理的Dahl岩井盐敏感大鼠，伴随着上调肾脏氧化应激，炎症和纤维化相关的标志物，如p22 phox，TGF-β，纤连蛋白，单核细胞趋化蛋白-1和1型胶原。然而，青春期前以及连续的奥美沙坦治疗恢复了抑制的肾脏ATRAP表达，并抑制了p22 phox，TGF-β，纤连蛋白，MCP-1和1型胶原蛋白的肾脏活化。在Dahl Iwai耐盐大鼠中，未观察到盐负荷对肾脏ATRAP表达的抑制或诱导肾脏病理反应。结论这些结果表明，青春期前短暂阻断AT 1 R信号对盐诱导的高血压和肾脏具有长期治疗作用盐敏感大鼠的肾脏损伤，部分原因是通过持续增强肾脏ATRAP表达，提示ATRAP是盐诱导的高血压和肾损伤的新分子靶点。J Hypertens 29：1919-1929（C）2011年威科健康垂直酒吧Lippincott威廉姆斯&威尔金斯。
Objective 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.Methods and results 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-beta, 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-beta, 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.Conclusions 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. J Hypertens 29:1919-1929 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.