| First Author | Lu TJ | Year | 2019 |
| Journal | Am J Physiol Renal Physiol | Volume | 317 |
| Issue | 7 | Pages | F30-F42 |
| PubMed ID | 30969802 | Mgi Jnum | J:280744 |
| Mgi Id | MGI:6369530 | Doi | 10.1152/ajprenal.00455.2018 |
| Citation | Lu TJ, et al. (2019) MST3 is involved in ENaC-mediated hypertension. Am J Physiol Renal Physiol 317(7):F30-F42 |
| abstractText | 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. |
