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Abstract: TH-PO515

WNK1 and WNK4 Form Heteromultimer to Regulate NCC In Vivo

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic


  • Xie, Jian, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
  • Yang, Yih-sheng, UT Southwestern Medical Center, Dallas, Texas, United States
  • Huang, Chou-Long, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States

Sodium reabsorption via the sodium-chloride cotransporter (NCC) in distal convoluted tubule (DCT) plays an important role in total body sodium homeostasis. In vitro, with-no-lysine (WNK) kinases WNK1 and WNK4 both activate NCC through intermediate STE20/SPS1-related proline- and alanine-rich kinase (SPAK) and related oxidative stress-responsive 1 (OSR1). It has been reported that WNK1 and 4 interact in vitro. Yet, it is believed that in vivo WNK4 is the main regulator of NCC, in part based on findings that Wnk4-null mice have a nearly complete loss of NCC activity. In addition, WNK4 is essential for stimulation of NCC by low dietary potassium intake through lowering the intracellular chloride concentration. The role of WNK1 in the regulation of NCC in vivo remains poorly understood.


Global Wnk1-null mice are embryonic lethal, due to loss of WNK1-OSR1/SPAK signaling in the vascular endothelium. To study the role of WNK1 in kidney, we generated a mouse model that expresses constitutive-active SPAK in a variety of tissues including vascular endothelium, but with virtually no expression in the kidney. This approach creates a viable mouse model with functionally kidney Wnk1-null.


Kidney Wnk1-null mice exhibit renal sodium wasting and little NCC activity compared to wildtype mice as assayed by thiazide-sensitive urinary Na excretion and phospho-NCC western blotting. Reciprocal co-immunoprecipitation experiments reveal that WNK1 and WNK4 form complexes in the kidney. Wnk4-null mice have minimal NCC activity and NCC activity is not stimulated by low dietary potassium intake. Unlike that in Wnk4-null mice, low dietary potassium intake stimulates NCC activity in kidney Wnk1-null mice.


Our results provide evidence supporting the notion that WNK1 and WNK4 form heteromultimers in vivo to regulate NCC. WNK4 is more sensitive than WNK1 to inhibition by intracellular chloride.


  • NIDDK Support