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

Jul 14, 2012American journal of physiology. Renal physiology

Kidney-specific WNK1 reduces sodium reabsorption in the kidney’s thick ascending limb

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Abstract

Kidney-specific WNK1 (KS-WNK1) expression was highest in the distal convoluted tubule (DCT) and enhanced by a high potassium diet.

KS-WNK1 was predominantly found in the DCT, followed by the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct.
A high potassium diet increased KS-WNK1 expression specifically in the DCT and cTAL.
Na(+) reabsorption in cTAL was greater in KS-WNK1-knockout mice compared to wild-type mice.
Wild-type mice on a high potassium diet showed reduced Na(+) reabsorption in cTAL, an effect that was absent in KS-WNK1-knockout mice.
Transgenic mice that overexpressed KS-WNK1 had lower Na(+) reabsorption in cTAL compared to wild-type mice.
A high potassium diet led to increased urine volume and urinary Na(+) and K(+) excretion in wild-type mice, with a reduced response in KS-WNK1-knockout mice.

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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.

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

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