Role of the WNK-activated SPAK kinase in regulating blood pressure.
Role of the WNK-activated SPAK kinase in regulating blood pressure.
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DOI：
10.1002/emmm.200900058
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发表时间：
2010-02
影响因子：
11.1
通讯作者：
Alessi, Dario R.
中科院分区：
文献类型：
--
作者：
Rafiqi, Fatema H.;Zuber, Annie Mercier;Glover, Mark;Richardson, Ciaran;Fleming, Stewart;Jovanovic, Sofija;Jovanovic, Aleksandar;O'Shaughnessy, Kevin M.;Alessi, Dario R.
无K（赖氨酸）（WNK）激酶内的突变导致戈登综合征，其特征为高血压和高钾血症。WNK激酶磷酸化并激活STE 20/SPS 1相关的脯氨酸/富含丙氨酸激酶（SPAK）蛋白激酶，该蛋白激酶磷酸化并刺激控制肾脏中盐重吸收的关键Na+：Cl−协同转运蛋白（NCC）和Na+：K+：2Cl−协同转运蛋白（NKCC 2）协同转运蛋白。为了确定该途径在调节血压中的重要性，我们产生了SPAK不能被WNK激活的敲入小鼠。SPAK基因敲入的动物是存活的，但显示出盐依赖性的显著降低的血压。这些动物在SPAK磷酸化的残基处NCC和NKCC 2共转运蛋白的磷酸化也显著降低。这也伴随着NCC和NKCC 2蛋白表达的减少，而信使RNA（mRNA）水平没有变化。在一个正常的Na+饮食，SPAK基因敲入小鼠是正常的血钾，但开发轻度低钾血症时，肾素-血管紧张素系统被激活的低Na+饮食。这些观察结果表明，SPAK在控制哺乳动物的血压中起着重要作用。我们的研究结果表明，SPAK抑制剂将通过降低NCC和NKCC 2的磷酸化以及表达来有效降低血压。请参见Maria Castañeda-Bagio和Gerald Gamba的特写（DOI 10.1002/emmm.200900059）。
Mutations within the with-no-K(Lys) (WNK) kinases cause Gordon's syndrome characterized by hypertension and hyperkalaemia. WNK kinases phosphorylate and activate the STE20/SPS1-related proline/alanine-rich kinase (SPAK) protein kinase, which phosphorylates and stimulates the key Na+:Cl− cotransporter (NCC) and Na+:K+:2Cl− cotransporters (NKCC2) cotransporters that control salt reabsorption in the kidney. To define the importance of this pathway in regulating blood pressure, we generated knock-in mice in which SPAK cannot be activated by WNKs. The SPAK knock-in animals are viable, but display significantly reduced blood pressure that was salt-dependent. These animals also have markedly reduced phosphorylation of NCC and NKCC2 cotransporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in messenger RNA (mRNA) levels. On a normal Na+-diet, the SPAK knock-in mice were normokalaemic, but developed mild hypokalaemia when the renin–angiotensin system was activated by a low Na+-diet. These observations establish that SPAK plays an important role in controlling blood pressure in mammals. Our results imply that SPAK inhibitors would be effective at reducing blood pressure by lowering phosphorylation as well as expression of NCC and NKCC2. See accompanying Closeup by Maria Castañeda-Bueno and Gerald Gamba (DOI 10.1002/emmm.200900059).
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影响因子：
19.6
作者：
Cai, H.;Cebotaru, V.;Guggino, W. B.
通讯作者：
Guggino, W. B.
影响因子：
4
作者：
Richardson, Ciaran;Alessi, Dario R.
通讯作者：
Alessi, Dario R.
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作者：
Michlig, S;Mercier, A;Firsov, D
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Firsov, D
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4.8
作者：
Schultheis, PJ;Lorenz, JN;Shull, GE
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Shull, GE
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16.2
作者：
Leiserson, WM;Harkins, EW;Keshishian, H
通讯作者：
Keshishian, H