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.