MST3 is involved in ENaC-mediated hypertension.

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.