Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct

Dec 1, 2012American journal of physiology. Renal physiology

Kidney WNK1 protein controls salt and potassium balance in mouse kidney tubules

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Abstract

KS-WNK1 knockout mice exhibited reduced K(+) secretion in the cortical collecting duct (CCD) compared to wild-type controls.

K(+) secretion was significantly lower in KS-WNK1 knockout CCD when perfused at a low fluid rate of ~1.5 nl/min.
Na(+) reabsorption and the lumen-negative transepithelial potential difference were also decreased in the KS-WNK1 knockout CCD.
Increasing the perfusion rate to ~5.5 nl/min enhanced K(+) secretion in both wild-type and knockout CCD.
The flow-stimulated increase in K(+) secretion was similar in both genotypes at the higher perfusion rate.
Iberiotoxin, a maxi-K(+) channel inhibitor, did not affect K(+) secretion at the lower flow rate but blocked the flow-dependent increase at the higher rate.
KS-WNK1 is associated with the regulation of Na(+) transport in the CCD.

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Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is a kinase-deficient variant of WNK1 that is expressed exclusively in the kidney. It is abundantly expressed in the distal convoluted tubule (DCT) and to a lesser extent in the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct (CCD). KS-WNK1 inhibits Na(+)-K(+)-2Cl(-)- and sodium chloride cotransporter-mediated Na(+) reabsorption in cTAL and DCT, respectively. Here, we investigated the role of KS-WNK1 in regulating Na(+) and K(+) transport in CCD using in vitro microperfusion of tubules isolated from KS-WNK1 knockout mice and control wild-type littermates. Because baseline K(+) secretion and Na(+) reabsorption were negligible in mouse CCD, we studied tubules isolated from mice fed a high-K(+) diet for 2 wk. Compared with that in wild-type tubules, K(+) secretion was reduced in KS-WNK1 knockout CCD perfused at a low luminal fluid rate of ~1.5 nl/min. Na(+) reabsorption and the lumen-negative transepithelial potential difference were also lower in the KS-WNK1 knockout CCD compared with control CCD. Increasing the perfusion rate to ~5.5 nl/min stimulated K(+) secretion in the wild-type as well as knockout CCD. The magnitudes of flow-stimulated increase in K(+) secretion were similar in wild-type and knockout CCD. Maxi-K(+) channel inhibitor iberiotoxin had no effect on K(+) secretion when tubules were perfused at ~1.5 nl/min, but completely abrogated the flow-dependent increase in K(+) secretion at ~5.5 nl/min. These findings support the notion that KS-WNK1 stimulates ROMK-mediated K(+) secretion, but not flow-dependent K(+) secretion mediated by maxi-K(+) channels in CCD. In addition, KS-WNK1 plays a role in regulating Na(+) transport in the CCD.

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Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct

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