Kir4.2 mediates proximal potassium effects on glutaminase activity and kidney injury
Andrew S. Terker, Yahua Zhang, Juan Pablo Arroyo, Shirong Cao, Suwan Wang, Xiaofeng Fan, Jerod S. Denton, Ming‐Zhi Zhang, Raymond C. Harris
Abstract
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.