SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation.
SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation.
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DOI：
10.1371/journal.pone.0072969
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lin SH
中科院分区：
文献类型：
--
作者：
Chu PY;Cheng CJ;Wu YC;Fang YW;Chau T;Uchida S;Sasaki S;Yang SS;Lin SH
OSR 1（氧化应激反应激酶-1）/SPAK [STE 20（无菌20）/SPS 1相关脯氨酸/富含丙氨酸激酶]-NCC（Na+-Cl−协同转运蛋白）信号级联的刺激在WNK [无赖氨酸（K）]激酶4 D561 A敲入小鼠II型假性醛固酮减少症（PHA II）模型中起重要作用，该模型以盐敏感性高血压和高钾血症为特征。本研究的目的是探讨Osr 1和Spak在体内PHA II发病机制中各自的作用。将Wnk 4 D561 A/+小鼠与肾小管特异性（KSP）Osr 1敲除（KSP-Osr 1-/-）和Spak敲除（Spak-/-）小鼠杂交。检测血压、血浆和尿液生化以及肾脏中相关蛋白的表达。Wnk 4 D561 A/+、KSP-Osr 1 −/−和Spak −/−小鼠分别重现了PHA II、Bartter样综合征和Gitelman综合征的表型。Wnk 4 D561 A/+. KSP-Osr 1 −/−保持PHA II表型，而Wnk 4 D561 A/+.Spak −/−小鼠血压正常，缺乏PHA II表型。在Wnk 4 D561 A/+和Wnk 4 D561 A/+. KSP-Osr 1 −/−小鼠中，磷酸化Spak和Ncc类似地增加，而在Wnk 4 D561 A/+.Spak −/−小鼠中，磷酸化Ncc正常化。此外，Wnk 4 D561 A/+. KSP-Osr 1 −/−小鼠对噻嗪类利尿剂的反应表现出过度的盐排泄，而Wnk 4 D561 A/+.Spak −/−小鼠则表现出正常反应。Wnk 4D 561 A/+.Spak −/−. KSP-Osr 1 −/−三重突变小鼠血压低，磷酸化Ncc减少。SPAK和OSR 1在维持血压中都很重要，但SPAK-NCC的激活在PHA II中起主导作用。SPAK可能是与WNK 4激活相关的盐敏感性高血压疾病的治疗靶点。
Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na+-Cl− cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo. Wnk4 D561A/+ mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP-Osr1 −/−) and Spak knockout (Spak −/−) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 D561A/+, KSP-Osr1 −/−, and Spak −/− mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 D561A/+.KSP-Osr1 −/− remained phenotypically PHA II while Wnk4 D561A/+.Spak −/− mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 D561A/+ and Wnk4 D561A/+.KSP-Osr1 −/− mice while phosphorylated Ncc normalized in Wnk4 D561A/+.Spak −/− mice. Furthermore, Wnk4 D561A/+.KSP-Osr1 −/− mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 D561A/+.Spak −/− mice exhibited normal responses. Wnk4D561A/+.Spak −/−.KSP-Osr1 −/− triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.
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DOI：
10.1152/ajprenal.00358.2009
发表时间：
2009-09-01
影响因子：
4.2
作者：
Ahlstrom, Robert;Yu, Alan S. L.
通讯作者：
Yu, Alan S. L.
影响因子：
13.2
作者：
Lin, SH;Cheng, NL;Halperin, ML
通讯作者：
Halperin, ML
影响因子：
5.8
作者：
Mayan, H;Vered, I;Farfel, Z
通讯作者：
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影响因子：
64.8
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Boyden, Lynn M.;Choi, Murim;Choate, Keith A.;Nelson-Williams, Carol J.;Farhi, Anita;Toka, Hakan R.;Tikhonova, Irina R.;Bjornson, Robert;Mane, Shrikant M.;Colussi, Giacomo;Lebel, Marcel;Gordon, Richard D.;Semmekrot, Ben A.;Poujol, Alain;Valimaki, Matti J.;De Ferrari, Maria E.;Sanjad, Sami A.;Gutkin, Michael;Karet, Fiona E.;Tucci, Joseph R.;Stockigt, Jim R.;Keppler-Noreuil, Kim M.;Porter, Craig C.;Anand, Sudhir K.;Whiteford, Margo L.;Davis, Ira D.;Dewar, Stephanie B.;Bettinelli, Alberto;Fadrowski, Jeffrey J.;Belsha, Craig W.;Hunley, Tracy E.;Nelson, Raoul D.;Trachtman, Howard;Cole, Trevor R. P.;Pinsk, Maury;Bockenhauer, Detlef;Shenoy, Mohan;Vaidyanathan, Priya;Foreman, John W.;Rasoulpour, Majid;Thameem, Farook;Al-Shahrouri, Hania Z.;Radhakrishnan, Jai;Gharavi, Ali G.;Goilav, Beatrice;Lifton, Richard P.
通讯作者：
Lifton, Richard P.
影响因子：
4.8
作者：
Grimm, P. Richard;Taneja, Tarvinder K.;Welling, Paul A.
通讯作者：
Welling, Paul A.