Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology , Tainan , Taiwan.
Department of Nephrology, Chi-Mei Medical Center , Tainan , Taiwan.
Am J Physiol Renal Physiol. 2019 Jul 1;317(7):F30-F42. doi: 10.1152/ajprenal.00455.2018. Epub 2019 Apr 10.
Liddle syndrome is an inherited form of human hypertension caused by increasing epithelial Na channel (ENaC) expression. Increased Na retention through ENaC with subsequent volume expansion causes hypertension. In addition to ENaC, the Na-K-Cl cotransporter (NKCC) and Na-Cl symporter (NCC) are responsible for Na reabsorption in the kidneys. Several Na transporters are evolutionarily regulated by the Ste20 kinase family. Ste20-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 phosphorylate downstream NKCC2 and NCC to maintain Na and blood pressure (BP) homeostasis. Mammalian Ste20 kinase 3 (MST3) is another member of the Ste20 family. We previously reported that reduced MST3 levels were found in the kidneys in spontaneously hypertensive rats and that MST3 was involved in Na regulation. To determine whether MST3 is involved in BP stability through Na regulation, we generated a MST3 hypomorphic mutation and designated MST3 and MST3 mice to examine BP and serum Na and K concentrations. MST3 mice exhibited hypernatremia, hypokalemia, and hypertension. The increased ENaC in the kidney played roles in hypernatremia. The reabsorption of more Na promoted more K secretion in the kidney and caused hypokalemia. The hypernatremia and hypokalemia in MST3 mice were significantly reversed by the ENaC inhibitor amiloride, indicating that MST3 mice reabsorbed more Na through ENaC. Furthermore, Madin-Darby canine kidney cells stably expressing kinase-dead MST3 displayed elevated ENaC currents. Both the in vivo and in vitro results indicated that MST3 maintained Na homeostasis through ENaC regulation. We are the first to report that MST3 maintains BP stability through ENaC regulation.
Liddle 综合征是一种遗传性人类高血压形式，由上皮钠通道 (ENaC) 表达增加引起。通过 ENaC 增加 Na 重吸收，随后发生容量扩张导致高血压。除了 ENaC，钠-钾-氯共转运体 (NKCC) 和钠-氯同向转运体 (NCC) 负责肾脏中的 Na 重吸收。几种 Na 转运体受 Ste20 激酶家族的进化调控。Ste20 相关脯氨酸/丙氨酸丰富激酶和氧化应激反应激酶-1 磷酸化下游 NKCC2 和 NCC，以维持 Na 和血压 (BP) 稳态。哺乳动物 Ste20 激酶 3 (MST3) 是 Ste20 家族的另一个成员。我们之前报道过自发性高血压大鼠肾脏中 MST3 水平降低，并且 MST3 参与 Na 调节。为了确定 MST3 是否通过 Na 调节参与 BP 稳定性，我们生成了 MST3 功能缺失突变，并将 MST3 和 MST3 小鼠命名为 MST3 和 MST3 以检查 BP 和血清 Na 和 K 浓度。MST3 小鼠表现出高钠血症、低钾血症和高血压。肾脏中 ENaC 的增加在高钠血症中起作用。肾脏中更多 Na 的重吸收促进了更多的 K 分泌，导致低钾血症。MST3 小鼠的高钠血症和低钾血症被 ENaC 抑制剂阿米洛利显著逆转，表明 MST3 小鼠通过 ENaC 重吸收更多的 Na。此外，稳定表达激酶失活 MST3 的 Madin-Darby 犬肾细胞显示出升高的 ENaC 电流。体内和体外结果均表明，MST3 通过调节 ENaC 维持 Na 内稳态。我们是第一个报道 MST3 通过调节 ENaC 维持 BP 稳定性的人。
