The distal convoluted tubule (DCT) plays a crucial role in potassium (K⁺) homeostasis, with electrogenic basolateral K⁺ flux well established as a regulator of its function. While the involvement of electroneutral basolateral K⁺ transport has been hypothesized, its precise role remains unclear. The electroneutral potassium chloride (Cl⁻) cotransporter, KCC3, is expressed in the kidney, but its role in DCT function has yet to be fully defined. To explore this, we generated a novel animal model with DCT-specific deletion of KCC3. Our results show that KCC3 deletion in DCT cells led to reduced levels of both total and phosphorylated NCC, along with decreased NCC mRNA expression, indicating a regulatory role for KCC3 in NCC expression at the transcript level. Despite these changes, knockout animals maintained normal electrolyte balance under standard dietary conditions. In response to dietary K⁺ restriction, knockout mice showed no significant differences compared to controls—blood K⁺ levels, NCC phosphorylation, and WNK body formation in the DCT remained unchanged. These findings suggest that KCC3 is involved in the basal regulation of NCC expression but is not essential for DCT adaptation to K⁺ depletion or for overall K⁺ homeostasis.
Inoue et al. (Thu,) studied this question.