title: Enhanced angiotensin receptor-associated protein in renal tubule suppresses angiotensin-dependent hypertension.
abstract: We have previously shown that angiotensin II type 1 receptor-associated protein (ATRAP/Agtrap) interacts with the angiotensin II type 1 receptor and promotes constitutive internalization of the receptor so as to inhibit the pathological activation of its downstream signaling but preserve baseline physiological signaling activity. The present study was designed to investigate the role of renal ATRAP in angiotensin II-dependent hypertension. We generated transgenic mice dominantly expressing ATRAP in the renal tubules, including renal distal tubules. The renal ATRAP transgenic mice exhibited no significant change in blood pressure at baseline on normal salt diet. However, in the renal ATRAP transgenic mice compared with wild-type mice, the following took place: (1) the development of high blood pressure in response to angiotensin II infusion was significantly suppressed based on radiotelemetry, (2) the extent of daily positive sodium balance was significantly reduced during angiotensin II infusion in metabolic cage analysis, and (3) the renal Na+ -Cl- cotransporter activation and α-subunit of the epithelial sodium channel induction by angiotensin II infusion were inhibited. Furthermore, adenoviral overexpression of ATRAP suppressed the angiotensin II-mediated increase in the expression of α-subunit of the epithelial sodium channel in mouse distal convoluted tubule cells. These results indicate that renal tubule-dominant ATRAP activation provokes no evident effects on blood pressure at baseline but exerts an inhibitory effect on the pathological elevation of blood pressure in response to angiotensin II stimulation, thereby suggesting that ATRAP is a potential target of interest in blood pressure modulation under pathological conditions.
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wakui
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsurumi-Ikeya
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujita
authors.forename: Akinobu
authors.initials: A
authors.lastname: Maeda
authors.forename: Masato
authors.initials: M
authors.lastname: Ohsawa
authors.forename: Kengo
authors.initials: K
authors.lastname: Azushima
authors.forename: Kazushi
authors.initials: K
authors.lastname: Uneda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nagahama
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D000804:Angiotensin II; D004247:DNA
keywords: angiotensin II; angiotensin receptors; basic science; gene expression/regulation; hypertension (kidney); membrane transport/ion channels; receptors