Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats

作者：Dejima Toru; Tamura Kouichi^*; Wakui Hiromichi; Maeda Akinobu; Ohsawa Masato; Kanaoka Tomohiko; Haku Sona; Kengo Azushima; Masuda Shin ichiro; Shigenaga Atsu ichiro; Azuma Koichi; Matsuda Miyuki; Yabana Machiko; Hirose Tomonori; Uchino Kazuaki; Kimura Kazuo; Nagashima Yoji; Umemura Satoshi

来源：Journal of Hypertension, 2011, 29(10): 1919-1929.

DOI：10.1097/HJH.0b013e32834a5a46

• angiotensin receptors
• basic science
• gene expression/regulation
• hypertension (kidney)
• oxidative stress (kidney)
• receptors
• salt-sensitive

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.

• 出版日期2011-10