| First Author | Yang YS | Year | 2018 |
| Journal | Am J Physiol Renal Physiol | Volume | 314 |
| Issue | 5 | Pages | F999-F1007 |
| PubMed ID | 29384416 | Mgi Jnum | J:281911 |
| Mgi Id | MGI:6367936 | Doi | 10.1152/ajprenal.00177.2017 |
| Citation | Yang YS, et al. (2018) Differential roles of WNK4 in regulation of NCC in vivo. Am J Physiol Renal Physiol 314(5):F999-F1007 |
| abstractText | The Na(+)-Cl(-) cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. The current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl(-) concentration ([Cl(-)]i). WNK kinases bind Cl(-), and Cl(-) binding decreases the catalytic activity. It is believed that hypokalemia under low K(+) intake decreases [Cl(-)]i to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl(-)]i. Whether [Cl(-)]i in DCT under low-K(+) diet is sufficiently low to activate WNK4 is unknown. Furthermore, increased luminal NaCl delivery also stimulates NCC and causes upregulation of the transporter. Unlike low K(+) intake, increased luminal NaCl delivery would tend to increase [Cl(-)]i. Thus we investigated the role of WNK4 and [Cl(-)]i in regulating NCC. We generated Wnk4-knockout mice and examined regulation of NCC by low K(+) intake and by increased luminal NaCl delivery in knockout (KO) and wild-type mice. Wnk4-KO mice have marked reduction in the abundance, phosphorylation, and functional activity of NCC vs. wild type. Low K(+) intake increases NCC phosphorylation and functional activity in wild-type mice, but not in Wnk4-KO mice. Increased luminal NaCl delivery similarly upregulates NCC, which, contrary to low K(+) intake, is not abolished in Wnk4-KO mice. The results reveal that modulation of WNK4 activity by [Cl(-)]i is not the sole mechanism for regulating NCC. Increased luminal NaCl delivery upregulates NCC via yet unknown mechanism(s) that may override inhibition of WNK4 by high [Cl(-)]i. |
