title: Intrarenal suppression of angiotensin II type 1 receptor binding molecule in angiotensin II-infused mice.
abstract: ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.
authors.affiliation: Dept. of Medical Science and Cardiorenal Medicine, Yokohama City Univ. 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: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Bai
authors.forename: Toru
authors.initials: T
authors.lastname: Dejima
authors.forename: Atsu-Ichiro
authors.initials: A
authors.lastname: Shigenaga
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.forename: Akinobu
authors.initials: A
authors.lastname: Maeda
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirose
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishigami
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.forename: Machiko
authors.initials: M
authors.lastname: Yabana
authors.forename: Susumu
authors.initials: S
authors.lastname: Minamisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000096:biosynthesis; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D053503:Epithelial Sodium Channels; C507047:Scnn1a protein, mouse; D000808:Angiotensinogen; D000804:Angiotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse