Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb

Am J Physiol Renal Physiol. 2012 Sep;303(5):F667-73. doi: 10.1152/ajprenal.00290.2012. Epub 2012 Jul 11.

Abstract

Kidney-specific WNK1 (KS-WNK1) is a variant of full-length WNK1. Previous studies have reported that KS-WNK1 is predominantly expressed in the distal convoluted tubule (DCT) where it regulates sodium-chloride cotransporter. The role of KS-WNK1 in other nephron segments is less clear. Here, we measured the expression of KS-WNK1 transcript in microdissected renal tubules and found that KS-WNK1 was most abundant in the DCT, followed by cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct. A high K(+) diet enhanced the expression of KS-WNK1 in the DCT and cTAL, selectively. It has been reported that a high-K diet suppresses Na(+) reabsorption in TAL. To understand the role of KS-WNK1 in Na(+) transport in cTAL and the regulation by dietary K(+), we examined Na(+) reabsorption using in vitro microperfusion in cTAL isolated from KS-WNK1-knockout mice and wild-type littermates fed either a control-K(+) or high-K(+) diet. Furosemide-sensitive Na(+) reabsorption in cTAL was higher in KS-WNK1-knockout (KO) mice than in wild-type. A high-K(+) diet inhibited Na(+) reabsorption in cTAL from wild-type mice, but the inhibition was eliminated in KS-WNK1-KO mice. We further examined the role of KS-WNK1 using transgenic mice that overexpress KS-WNK1. Na(+) reabsorption in cTAL was lower in transgenic than in wild-type mice. In whole animal clearance studies, a high-K(+) diet increased daily urine volume and urinary Na(+) and K(+) excretion in wild-type mice, which was blunted in KS-WNK1-KO mice. Thus KS-WNK1 inhibits Na(+) reabsorption in cTAL and mediates the inhibition of Na(+) reabsorption in the segment by a high-K diet.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Furosemide / pharmacology
  • Kidney Tubules, Distal / metabolism*
  • Loop of Henle / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Potassium, Dietary / pharmacology
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / physiology*
  • Sodium / metabolism*
  • WNK Lysine-Deficient Protein Kinase 1

Substances

  • Minor Histocompatibility Antigens
  • Potassium, Dietary
  • Furosemide
  • Sodium
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse