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

Abstract

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.