Macrophage SPAK deletion limits a low potassium-induced kidney inflammatory program.

Inadequate dietary potassium (K(+)) consumption is a significant contributor to poor cardiovascular outcomes. A diet with reduced K(+) content has been shown to cause salt-sensitive increases in blood pressure. More recently, we have also shown that reductions in blood K(+) can cause direct kidney injury, independent of dietary sodium (Na(+)) content. Here, we investigated the role of the kinase Ste20p-related proline-alanine-rich kinase (SPAK) in this kidney injury response. We observed that global SPAK deletion protected the kidney from the damaging effects of a diet high in Na(+) and low in K(+). We hypothesized that kidney macrophages were contributing to the injury response and that macrophage-expressed SPAK is essential in this process. We observed SPAK protein expression in isolated macrophages in vitro. Culture in K(+)-deficient medium increased SPAK phosphorylation and caused SPAK to localize to cytosolic puncta, reminiscent of with-no-lysine kinase (WNK) bodies identified along the distal nephron epithelium. WNK1 also adopted a punctate staining pattern under low K(+) conditions, and SPAK phosphorylation was prevented by treatment with the WNK inhibitor WNK463. Macrophage-specific SPAK deletion in vivo protected against the low K(+)-mediated renal inflammatory and fibrotic responses. Our results highlight an important role for macrophages and macrophage-expressed SPAK in the propagation of kidney damage that occurs in response to reduced dietary K(+) consumption.NEW & NOTEWORTHY Global Ste20p-related proline alanine-rich kinase (SPAK) deletion protects against harmful kidney effects of dietary K(+) deficiency. Exposure to low K(+) conditions increases SPAK phosphorylation and induces SPAK to adopt a punctate staining pattern. Macrophage-specific deletion of SPAK confers protection to low K(+)-induced kidney injury in vivo. Macrophage-expressed SPAK plays a key role in the development of kidney injury in response to a low K(+) diet.