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

Am J Physiol Renal Physiol. 2024 Nov 1;327(5):F899-F909. doi: 10.1152/ajprenal.00175.2024. Epub 2024 Sep 19.

Abstract

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.

Keywords: SPAK; WNK kinase; kidney injury; macrophage; potassium.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Kidney* / drug effects
  • Kidney* / metabolism
  • Kidney* / pathology
  • Macrophages* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Nephritis / chemically induced
  • Nephritis / genetics
  • Nephritis / metabolism
  • Nephritis / pathology
  • Nephritis / prevention & control
  • Phosphorylation
  • Potassium Deficiency / genetics
  • Potassium Deficiency / metabolism
  • Potassium, Dietary / metabolism
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • WNK Lysine-Deficient Protein Kinase 1 / genetics
  • WNK Lysine-Deficient Protein Kinase 1 / metabolism

Substances

  • Protein Serine-Threonine Kinases
  • Stk39 protein, mouse
  • Potassium, Dietary
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse