SPAK-Knockout Mice Manifest Gitelman Syndrome and Impaired Vasoconstriction

被引:239
作者
Yang, Sung-Sen [1 ,2 ,3 ]
Lo, Yi-Fen [2 ]
Wu, Chin-Chen [4 ]
Lin, Shu-Wha [5 ]
Yeh, Chien-Ju [1 ]
Chu, Pauling [1 ,2 ]
Sytwu, Huey-Kang [2 ]
Uchida, Shinichi [6 ]
Sasaki, Sei [6 ]
Lin, Shih-Hua [1 ,2 ]
机构
[1] Tri Serv Gen Hosp, Div Nephrol, Dept Med, Taipei, Taiwan
[2] Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan
[3] Natl Def Med Ctr, Grad Inst Physiol, Taipei, Taiwan
[4] Natl Def Med Ctr, Dept Pharmacol, Taipei, Taiwan
[5] Natl Taiwan Univ, Grad Inst Med Technol, Taipei 10764, Taiwan
[6] Tokyo Med & Dent Univ, Dept Nephrol, Grad Sch Med, Tokyo, Japan
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2010年 / 21卷 / 11期
关键词
VASCULAR SMOOTH-MUSCLE; NA-CL COTRANSPORTER; BLOOD-PRESSURE; NA+-K+-2CL(-) COTRANSPORTER; NA-K-2CL COTRANSPORTER; HYPOKALEMIC ALKALOSIS; BARTTERS-SYNDROME; WNK KINASES; HYPERTENSION; OSR1;
D O I
10.1681/ASN.2009121295
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Polymorphisms in the gene encoding sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) associate with hypertension susceptibility in humans SPAK interacts with WNK kinases to regulate the Na+-K+ 2Cl(-) and Na+-Cl- co-transporters [collectively, N(K)CC] Mutations in WNK1/4 and N(K)CC can cause changes in BP and dyskalemia in humans but the physiologic role of SPAK in vivo is unknown We generated and analyzed SPAK null mice by targeting disruption of exons 9 and 10 of SPAK Compared with SPAK(+/+) littermates, SPAK(+/-) mice exhibited hypotension without significant electrolyte abnormalities, and SPAK(-/-) mice not only exhibited hypotension but also recapitulated Gitelman syndrome with hypokalemia hypomagnesemia, and hypocalciuria In the kidney tissues of SPAK(-/-) mice the expression of total and phosphorylated (p)NCC was markedly decreased, but that of p-OSR1 total NKCC2, and p NKCC2 was significantly increased We observed a blunted response to thiazide but normal response to furosemide in SPAK(-/-) mice In aortic tissues total NKCC1 expression was increased but p-NKCC1 was decreased in SPAK-deficient mice Both SPAK(+/-) and SPAK(-/-) mice had impaired responses to the selective alpha(1)-adrenergic agonist phenylephrine and the NKCC1 inhibitor bumetanide suggesting that impaired aortic contractility may contribute to the hypotension of SPAK null mice In summary, SPAK-null mice have defects of NCC in the kidneys and NKCC1 in the blood vessels, leading to hypotension through renal salt wasting and vasodilation SPAK may be a promising target for antihypertensive therapy
引用
收藏
页码:1868 / 1877
页数:10
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