Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10750-5. doi: 10.1073/pnas.1104271108. Epub 2011 Jun 13.
Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca(2+)-dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca(2+) influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3-mediated Ca(2+) influx in vascular smooth muscle cells (VSMCs) in response to α-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca(2+) influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension.
丝氨酸-苏氨酸激酶无赖氨酸 4（WNK4）中的突变导致假性醛固酮增多症 2 型（PHAII），这是一种人类高血压的孟德尔形式。WNK4 调节肾脏中的多种离子转运体，而肾脏转运体的失调被认为是 WNK4 突变相关高血压的主要原因。另一个决定高血压的因素是血管张力，它由钙依赖性血管收缩调节。然而，WNK4 在血管收缩中的作用作为其调节血压功能的一部分尚不清楚。在这里，我们报告 WNK4 通过限制血管中的瞬时受体电位经典型 3（TRPC3）通道的钙内流，是一种独特的血压调节剂。WNK4 缺失显着增强了血管平滑肌细胞（VSMCs）中 TRPC3 介导的钙内流，以响应 α-肾上腺素能受体刺激，这是阻力动脉中高血压的病理标志。值得注意的是，WNK4 耗竭通过 TRPC3 介导的钙内流诱导 VSMCs 中的肥大细胞生长，并增加小肠系膜动脉的血管收缩。此外，携带导致 PHAII 的 Q562E 突变或无激酶活性的 D318A 突变的 WNK4 突变体无法介导 TRPC3 抑制。这些结果定义了 WNK4 的一个以前未描述的功能，并揭示了一个独特的治疗靶点，以控制 WNK4 相关高血压中的血压。
