Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.

Abstract

We recently generated Wnk4(D561A/+) knockin mice and found that a major pathogenesis of pseudohypoaldosteronism type II was the activation of the OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade by the mutant WNK4. However, the physiological roles of wild-type WNK4 on the regulation of Na excretion and blood pressure, and whether wild-type WNK4 functions positively or negatively in this cascade, remained to be determined. In the present study, we generated WNK4 hypomorphic mice by deleting exon 7 of the Wnk4 gene. These mice did not show hypokalemia and metabolic alkalosis, but they did exhibit low blood pressure and increased Na and K excretion under low-salt diet. Phosphorylation of OSR1/SPAK and NCC was significantly reduced in the mutant mice as compared with their wild-type littermates. Protein levels of ROMK and Maxi K were not changed, but epithelial Na channel appeared to be activated as a compensatory mechanism for the reduced NCC function. Thus, wild-type WNK4 is a positive regulator for the WNK-OSR1/SPAK-NCC cascade, and WNK4 is a potential target of anti-hypertensive drugs.

• Authors: Akihito Ohta, Tatemitsu Rai, Naofumi Yui, Motoko Chiga, Sung-Sen Yang, Shih-Hua Lin, Eisei Sohara, Sei Sasaki, Shinichi Uchida
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 18 Issue 20 Pg. 3978-86 (Oct 15 2009) ISSN: 1460-2083 [Electronic] England
• PMID: 19633012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Drug
• Slc12a3 protein, mouse
• Solute Carrier Family 12, Member 3
• Symporters
• Sodium
• Prkwnk4 protein, mouse
• Stk39 protein, mouse
• Protein Serine-Threonine Kinases
• Potassium

Topics

• Amino Acid Sequence
• Animals
• Biological Transport
• Blood Pressure
• Disease Models, Animal
• Female
• Gene Silencing
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Phosphorylation
• Potassium (metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Pseudohypoaldosteronism (genetics, metabolism, physiopathology)
• Receptors, Drug (genetics, metabolism)
• Sodium (metabolism)
• Solute Carrier Family 12, Member 3
• Symporters (genetics, metabolism)