Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb.
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.
Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8856, USA.
Chih-Jen
CJ
Cheng
Thao
T
Truong
Michel
M
Baum
Chou-Long
CL
Huang
D000818:Animals; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D008138:Loop of Henle / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D017419:Potassium, Dietary / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
D015778:Minor Histocompatibility Antigens; D017419:Potassium, Dietary; D005665:Furosemide; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse