Kir4.2 mediates proximal potassium effects on glutaminase activity and kidney injury

Inadequate potassium (K⁺) consumption correlates with increased mortality and poor cardiovascular outcomes. Potassium effects on blood pressure have been described previously; however, whether or not low K⁺ independently affects kidney disease progression remains unclear. Here, we demonstrate that dietary K⁺ deficiency causes direct kidney injury. Effects depend on reduced blood K⁺ and are kidney specific. In response to reduced K⁺, the channel Kir4.2 mediates altered proximal tubule (PT) basolateral K⁺ flux, causing intracellular acidosis and activation of the enzyme glutaminase and the ammoniagenesis pathway. Deletion of either Kir4.2 or glutaminase protects from low-K⁺ injury. Reduced K⁺ also mediates injury and fibrosis in a model of aldosteronism. These results demonstrate that the PT epithelium, like the distal nephron, is K⁺ sensitive, with reduced blood K⁺ causing direct PT injury. Kir4.2 and glutaminase are essential mediators of this injury process, and we identify their potential for future targeting in the treatment of chronic kidney disease.