G protein-coupled receptor kinase 4 gene variants in human essential hypertension
G protein-coupled receptor kinase 4 gene variants in human essential hypertension
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DOI：
10.1073/pnas.062694599
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发表时间：
2002-03-19
影响因子：
11.1
通讯作者：
Jose, PA
中科院分区：
文献类型：
--
作者：
Felder, RA;Sanada, H;Jose, PA
原发性高血压的遗传度高达30-50%，但其遗传原因(S)经深入调查仍未确定。肾多巴胺能系统在维持水和电解质平衡中起着关键作用，参与了遗传性高血压的发病机制。在遗传性高血压中，多巴胺和D-1类激动剂增加尿钠排泄的能力受到损害。D-1多巴胺受体与肾脏近端小管G蛋白/效应酶复合体之间的偶联缺陷是遗传性啮齿动物和人类高血压肾脏多巴胺能作用受损的原因。我们现在报道，在人类高血压中，G蛋白偶联受体激酶GRK4Gamma的单核苷酸多态性增加了G蛋白偶联受体激酶(GRK)的活性，并导致D-1受体在肾脏近端小管和转基因中国仓鼠卵巢细胞中从其G蛋白/效应酶复合体中丝氨酸磷酸化和解偶联。此外，在转基因小鼠中表达GRK4GammaA142V而不是野生型基因会产生高血压，并损害D-1样激动剂刺激的利尿和利钠作用，但不会产生降压作用。这些发现提供了肾脏D-1受体偶联缺陷的机制，并可能解释遗传性高血压肾脏无法正常排泄钠的原因。
Essential hypertension has a heritability as high as 30-50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D-1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D-1 dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4gamma, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D-1 receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4gammaA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D-1-like agonist stimulation. These findings provide a mechanism for the D-1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.