Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney

Biosci Rep. 2018 Jan 30;38(1):BSR20171243. doi: 10.1042/BSR20171243. Print 2018 Feb 28.


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.

Keywords: chloride; hypertension; intracellular signaling; molecular basis of health and disease; renal physiology; transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / genetics*
  • Chloride Channels / genetics*
  • Disease Models, Animal
  • Humans
  • Hypertension / genetics*
  • Hypertension / pathology
  • Kidney / metabolism
  • Membrane Proteins / genetics*
  • Mice
  • Phosphorylation
  • Potassium / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Signal Transduction / genetics
  • Sodium-Potassium-Chloride Symporters / genetics*
  • Solute Carrier Family 12, Member 3 / genetics


  • Bsnd protein, mouse
  • Chloride Channels
  • Clcnka protein, mouse
  • Membrane Proteins
  • Slc12a3 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 3
  • Prkwnk4 protein, mouse
  • Stk39 protein, mouse
  • Protein Serine-Threonine Kinases
  • Potassium