title: Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II.
abstract: Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 phosphorylation cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 phosphorylation cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet-induced phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK-SPAK-NKCC1 phosphorylation cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK-SPAK-NKCC1 phosphorylation cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II-induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this cascade could, therefore, be a novel therapeutic target in hypertension.
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan. esohara.kid@tmd.ac.jp.
authors.forename: Moko
authors.initials: M
authors.lastname: Zeniya
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Koichiro
authors.initials: K
authors.lastname: Susa
authors.forename: Takayasu
authors.initials: T
authors.lastname: Mori
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Oi
authors.forename: Motoko
authors.initials: M
authors.lastname: Chiga
authors.forename: Daiei
authors.initials: D
authors.lastname: Takahashi
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012982:Sodium, Dietary; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C578878:Slc12a2 protein, mouse; D012982:Sodium, Dietary; D064506:Solute Carrier Family 12, Member 2; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; C507511:Wnk3 protein, mouse; D014633:Valine
keywords: NKCC1; SPAK; WNK; angiotensin II; aorta