INSERM U970, Paris Cardiovascular Research Center PARCC, 56 rue Leblanc, 75015 Paris, France.
Hypertension. 2011 Sep;58(3):439-45. doi: 10.1161/HYPERTENSIONAHA.111.172429. Epub 2011 Jul 18.
Gain-of-function mutations in the human WNK1 (with-no-lysine[K]1) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1(+/-) haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1(+/-) mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α(1)-adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1(+/-) arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na(+)-K(+)-2Cl(-) cotransporter 1) in Wnk1(+/-) arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α(1)-adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α(1)-adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension.
WNK1（无赖氨酸[K]1）基因的功能获得性突变可导致一种单基因形式的动脉高血压，WNK1 多态性与常见的原发性高血压有关。WNK1 在肾脏离子重吸收中的作用已经确立，但迄今为止尚未对其对血管张力（血压的基本决定因素）的可能影响进行任何研究。WNK1 在小鼠中的完全失活是胚胎致死的。因此，我们在 Wnk1(+/-)杂合子不足的成年小鼠中检查了 WNK1 是否可以调节体内血管张力，以及这是否与血压变化相关。Wnk1(+/-) 小鼠表现出体内血压反应和α(1)-肾上腺素能受体激活后的血管收缩明显降低，而基础血压和肾功能没有变化。我们还观察到 Wnk1(+/-) 动脉中的压力诱导收缩（肌源性）反应的主要丧失，这与平滑肌细胞收缩功能的特定改变有关。这些血管张力的改变与 WNK1 底物 SPAK（STE20/SPS1 相关脯氨酸/丙氨酸丰富激酶）和其靶标 NKCC1（Na(+)-K(+)-2Cl(-)共转运蛋白 1）的磷酸化水平降低有关在 Wnk1(+/-) 动脉中。我们的研究确定了 WNK1 在维持体内血压和特定于α(1)-肾上腺素能受体激活的血管收缩反应中的新的主要作用。我们的发现揭示了一种新的血管信号通路，将α(1)-肾上腺素能受体和压力与 WNK1、SPAK 和 NKCC1 联系起来，从而可能大大拓宽对动脉高血压中血管张力调节机制的理解。
