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

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.