Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels

Clin Exp Nephrol. 2012 Aug;16(4):530-8. doi: 10.1007/s10157-012-0590-x.

Abstract

Background: We found that a mechanism of hypertension in pseudohypoaldosteronism type II (PHAII) caused by a WNK4 missense mutation (D561A) was activation of the WNK-OSR1/SPAK-NCC signal cascade. However, the pathogenic effect of intronic deletions in WNK1 genes also observed in PHAII patients remains unclear. To understand the pathophysiological roles of WNK1 in vivo, WNK1(+/-)mice have been analyzed, because homozygous WNK1 knockout is embryonic lethal. Although WNK1(+/-) mice have been reported to have hypotension, detailed analyses of the WNK signal cascade in the kidney and other organs of WNK1(+/-) mice have not been performed.

Method: We assess the effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels.

Results: Contrary to the previous report, the blood pressure of WNK1(+/-) mice was not decreased, even under a low-salt diet. Under a WNK4(D561A/+) background, the heterozygous deletion of the WNK1 gene did not reduce the high blood pressure either. We then evaluated the phosphorylation status of OSR1, SPAK, NCC, NKCC1, and NKCC2 in the kidney, but no significant decrease in the phosphorylation was observed in WNK1(+/-) mice or WNK1(+/-)WNK4(D561A/+) mice. In contrast, a significant decrease in NKCC1 phosphorylation in the aorta and a decreased pressure-induced myogenic response in the mesenteric arteries were observed in WNK1(+/-) mice.

Conclusion: The contribution of WNK1 to total WNK kinase activity in the kidney may be small, but that WNK1 may play a substantial role in the regulation of blood pressure in the arteries.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / physiology
  • Blood Vessels / physiology*
  • Disease Models, Animal
  • Endothelium, Vascular / physiopathology
  • Gene Deletion*
  • Heterozygote*
  • Hypertension / physiopathology
  • Kidney / blood supply
  • Kidney / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Muscle, Smooth, Vascular / physiopathology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / physiology*
  • Pseudohypoaldosteronism / physiopathology
  • Receptors, Drug / physiology
  • Signal Transduction / physiology*
  • Sodium-Potassium-Chloride Symporters / physiology
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 2
  • Solute Carrier Family 12, Member 3
  • Symporters / physiology
  • Transcription Factors / physiology*
  • WNK Lysine-Deficient Protein Kinase 1

Substances

  • Minor Histocompatibility Antigens
  • Osr1 protein, mouse
  • Receptors, Drug
  • Slc12a1 protein, mouse
  • Slc12a2 protein, mouse
  • Slc12a3 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 2
  • Solute Carrier Family 12, Member 3
  • Symporters
  • Transcription Factors
  • Stk39 protein, mouse
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse