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, SPAK, in this kidney injury response. We observed that global SPAK deletion protected the kidney from damaging effects of a diet high in Na+ and low in K+. We hypothesized 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 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.
Keywords: SPAK; WNK kinase; kidney injury; macrophage; potassium.