Abstract
The sodium chloride cotransporter (NCC) has been identified as a key molecule regulating potassium balance. The mechanisms of NCC regulation during low extracellular potassium concentrations have been studied in vitro. These studies have shown that hyperpolarization increased chloride efflux, leading to the activation of chloride-sensitive with-no-lysine kinase (WNK) kinases and their downstream molecules, including STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NCC. However, this mechanism was not studied in vivo. Previously, we developed the barttin hypomorphic mouse (Bsndneo/neo mice), expressing very low levels of barttin and ClC-K channels, because barttin is an essential β-subunit of ClC-K. In contrast with Bsnd−/− mice, Bsndneo/neo mice survived to adulthood. In Bsndneo/neo mice, SPAK and NCC activation after consuming a low-potassium diet was clearly impaired compared with that in wild-type (WT) mice. In ex vivo kidney slice experiment, the increase in pNCC and SPAK in low-potassium medium was also impaired in Bsndneo/neo mice. Furthermore, increased blood pressure was observed in WT mice fed a high-salt and low-potassium diet, which was not evident in Bsndneo/neo mice. Thus, our study provides in vivo evidence that, in response to a low-potassium diet, ClC-K and barttin play important roles in the activation of the WNK4-SPAK-NCC cascade and blood pressure regulation.
Highlights
Hypertension is a major worldwide public health problem associated with a variety of complications including stroke, heart failure, and kidney failure
We found that both pNCC and total NCC (tNCC) were more abundant in the kidneys of WT mice consuming high-salt and low-K (HSLK) diet than those maintained upon high-salt and normal-K (HSNK) diet (Figure 2B)
The slope of the regression lines was significantly greater in WT mice than in Bsndneo/neo mice (P=0.020). These results indicate that the activation of WNK4-SPS1-related proline/alanine-rich kinase (SPAK)-sodium chloride cotransporter (NCC) cascade in response to a low-K+ diet is dependent upon ClC-K function
Summary
Hypertension is a major worldwide public health problem associated with a variety of complications including stroke, heart failure, and kidney failure. Diets play a strong contributory role in blood pressure. The sodium (Na+) chloride (Cl−) cotransporter (NCC) expressed in the distal convoluted tubules (DCT) in the kidney plays an important role in the regulation of urinary K+ excretion, as well as in blood pressure regulation by NaCl reabsorption. A low-K+ diet increased the total amount and the phosphorylation of NCC [4,5,6,7,8,9] and elevated blood pressure [4,10]. This elevation of blood pressure with a low-K+ diet was dependent upon NCC, because NCC−/− mice did not show an elevation of blood pressure when under a low-K+ diet [4]. The notion that the NCC is important for regulating K+ excretion is supported by the facts that two genetic diseases, Gitelman syndrome (caused by the loss-of-function of NCC) and pseudohypoaldosteronism type II (caused by the gain-of-function of NCC)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
