| First Author | Ferdaus MZ | Year | 2024 |
| Journal | Am J Physiol Renal Physiol | Volume | 327 |
| Issue | 3 | Pages | F373-F385 |
| PubMed ID | 38961847 | Mgi Jnum | J:358386 |
| Mgi Id | MGI:7780226 | Doi | 10.1152/ajprenal.00101.2024 |
| Citation | Ferdaus MZ, et al. (2024) Deletion of KS-WNK1 promotes NCC activation by increasing WNK1/4 abundance. Am J Physiol Renal Physiol 327(3):F373-F385 |
| abstractText | Dietary potassium deficiency causes stimulation of sodium reabsorption leading to an increased risk in blood pressure elevation. The distal convoluted tubule (DCT) is the main rheostat linking plasma K(+) levels to the activity of the Na-Cl cotransporter (NCC). This occurs through basolateral membrane potential sensing by inwardly rectifying K(+) channels (Kir4.1/5.1); decrease in intracellular Cl(-); activation of WNK4 and interaction and phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK); binding of calcium-binding protein 39 (cab39) adaptor protein to SPAK, leading to its trafficking to the apical membrane; and SPAK binding, phosphorylation, and activation of NCC. As kidney-specific with-no-lysine kinase 1 (WNK1) isoform (KS-WNK1) is another participant in this pathway, we examined its function in NCC regulation. We eliminated KS-WNK1 specifically in the DCT and demonstrated increased expression of WNK4 and long WNK1 (L-WNK1) and increased phosphorylation of NCC. As in other KS-WNK1 models, the mice were not hyperkalemic. Although wild-type mice under low-dietary K(+) conditions demonstrated increased NCC phosphorylation, the phosphorylation levels of the transporter, already high in KS-WNK1, did not change under the low-K(+) diet. Thus, in the absence of KS-WNK1, the transporter lost its sensitivity to low plasma K(+). We also show that under low K(+) conditions, in the absence of KS-WNK1, there was no formation of WNK bodies. These bodies were observed in adjacent segments, not affected by the targeting of KS-WNK1. As our data are overall consistent with those of the global KS-WNK1 knockout, they indicate that the DCT is the predominant segment affecting the salt transport regulated by KS-WNK1.NEW & NOTEWORTHY In this paper, we show that KS-WNK1 is a critical component of the distal convoluted tubule (DCT) K(+) switch pathway. Its deletion results in an inability of the DCT to sense changes in plasma potassium. Absence of KS-WNK1 leads to abnormally high levels of WNK4 and L-WNK1 in the DCT, resulting in increased Na-Cl phosphorylation and function. Our data are consistent with KS-WNK1 targeting WNK4 and L-WNK1 to degradation. |
