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

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 <i>in vitro.</i> 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 <i>in vivo</i> Previously, we developed the barttin hypomorphic mouse (<i>Bsnd^neo/neo</i> mice), expressing very low levels of barttin and ClC-K channels, because barttin is an essential β-subunit of ClC-K. In contrast with <i>Bsnd^-/-</i> mice, <i>Bsnd^neo/neo</i> mice survived to adulthood. In <i>Bsnd^neo/neo</i> mice, SPAK and NCC activation after consuming a low-potassium diet was clearly impaired compared with that in wild-type (WT) mice. In <i>ex vivo</i> kidney slice experiment, the increase in pNCC and SPAK in low-potassium medium was also impaired in <i>Bsnd^neo/neo</i> mice. Furthermore, increased blood pressure was observed in WT mice fed a high-salt and low-potassium diet, which was not evident in <i>Bsnd^neo/neo</i> mice. Thus, our study provides <i>in vivo</i> 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.