Deletion of the angiotensin II type 1 receptor-associated protein enhances renal sodium reabsorption and exacerbates angiotensin II-mediated hypertension.
Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) promotes AT1R internalization along with suppression of pathological activation of tissue AT1R signaling. However, the functional significance of ATRAP in renal sodium handling and blood pressure regulation under pathological stimuli is not fully resolved. Here we show the blood pressure of mice with a gene-targeted disruption of ATRAP was comparable to that of wild-type mice at baseline. However, in ATRAP-knockout mice, angiotensin II-induced hypertension was exacerbated and the extent of positive sodium balance was increased by angiotensin II. Renal expression of the sodium-proton antiporter 3, a major sodium transporter in the proximal tubules, urinary pH, renal angiotensinogen production, and angiotensin II content was unaffected. Stimulation of the renal expression and activity of the epithelial sodium channel (ENaC), a major sodium transporter in the distal tubules, was significantly enhanced by chronic angiotensin II infusion. The circulating and urinary aldosterone levels were comparable. The blood pressure response and renal ENaC expression by aldosterone were not affected. Thus, ATRAP deficiency exacerbated angiotensin II-mediated hypertension by pathological activation of renal tubular AT1R by angiotensin II. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone-independent manner.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Masato
M
Ohsawa
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kouichi
K
Tamura
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Hiromichi
H
Wakui
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Akinobu
A
Maeda
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Toru
T
Dejima
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Tomohiko
T
Kanaoka
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kengo
K
Azushima
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kazushi
K
Uneda
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yuko
Y
Tsurumi-Ikeya
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Ryu
R
Kobayashi
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Miyuki
M
Matsuda
Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Shinichi
S
Uchida
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yoshiyuki
Y
Toya
Department of Pharmacology, Kagawa University School of Medicine, Kagawa, Japan.
Hiroyuki
H
Kobori
Department of Pharmacology, Kagawa University School of Medicine, Kagawa, Japan.
Akira
A
Nishiyama
Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Akio
A
Yamashita
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yoshihiro
Y
Ishikawa
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Satoshi
S
Umemura
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000450:Aldosterone / Q000097:blood / Q000652:urine; D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D053503:Epithelial Sodium Channels / Q000187:drug effects; D017353:Gene Deletion; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D065608:Renal Reabsorption / Q000187:drug effects* / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D016482:Urinalysis; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D000450:Aldosterone; D012964:Sodium