title: An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model.
abstract: Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension-resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel α-subunit and tumor necrosis factor-α was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease.
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: hiro1234@yokohama-cu.ac.jp.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wakui
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Azushima
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Uneda
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Sona
authors.initials: S
authors.lastname: Haku
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Haruhara
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kinguchi
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ohsawa
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.affiliation: Department of Pharmacology, Kagawa University School of Medicine, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeshima
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: tamukou@med.yokohama-cu.ac.jp.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D015536:Down-Regulation; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism*; D012083:Renin / Q000097:blood / Q000378:metabolism; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C544066:Agtr1a protein, mouse; C119712:Agtrap protein, mouse; D053503:Epithelial Sodium Channels; D044140:Receptor, Angiotensin, Type 1; C507047:Scnn1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D012083:Renin
keywords: chronic kidney disease; hypertension; renal tubules; renin–angiotensin system