The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy.
The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy.
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DOI：
10.1152/ajprenal.00132.2016
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Mohammed Z. Ferdaus;J. McCormick
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文献类型：
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作者：
Mohammed Z. Ferdaus;J. McCormick
慢性高血压（高血压）是美国最常见的疾病。虽然有几类药物可以治疗它，但许多患者（多达1000万美国人）对治疗反应不佳，即使使用多种药物。最近的证据表明，相当一部分患者将始终保持高血压，尽管最大的治疗与目前可用的药物。因此，迫切需要开发新的抗高血压药物。一个局限性是新靶点的识别，最近对单基因型高血压潜在机制的了解已经克服了这一局限性。家族性高钾血症性高血压是由无赖氨酸（WNK）激酶1和4以及cullin-3和kelch样3（促进WNK激酶降解的E3泛素连接酶复合物的组分）突变引起的。对该途径调节血压的机制的研究已经确定了几种用于开发新的抗高血压药物的候选药物。该途径特别有吸引力，因为其抑制不仅可以减少沿沿着多个节段的肾钠重吸收，而且还可以降低血管张力。在这里，我们将描述这一途径调节血压的机制，并讨论靶向它开发新的抗高血压药物的潜力。
Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension. The disease familial hyperkalemic hypertension is caused by mutations in with-no-lysine (WNK) kinases 1 and 4 and in cullin-3 and kelch-like 3, components of an E3 ubiquitin ligase complex that promotes WNK kinase degradation. The study of the mechanisms by which this pathway regulates blood pressure has identified several candidates for the development of new antihypertensive agents. This pathway is particularly attractive since its inhibition may not only reduce renal sodium reabsorption along multiple segments but may also reduce vascular tone. Here, we will describe the mechanisms by which this pathway regulate blood pressure and discuss the potential of targeting it to develop new antihypertensive drugs.