Figure 7. Model of low-K⁺ kidney injury.

In WT animals, low K⁺ causes increased basolateral K⁺ efflux through Kir4.2, reducing intracellular K⁺ (K⁺_i) and pH_i. This increases glutamine uptake along the basolateral membrane and its catabolism through GLS, producing ammonia, which is secreted into the lumen via NHE3. Glutamate dehudrogenase (GLUD) catalyzes conversion to α-ketoglutarate (α-KG). Metabolic flux through this pathway is increased under low-K⁺ conditions, causing increased kidney hypertrophy, inflammation, injury, and fibrosis. Kir4.2 deletion prevents alterations in basolateral K⁺ flux under low-K⁺ conditions. Kir4.2^−/− mice do not develop intracellular acidosis or increased glutamine catabolism and are protected from kidney hypertrophy and injury. While GLS knockout mice do develop an intracellular acidosis under low-K⁺ conditions, the absence of GLS prevents increased glutamine catabolism, affording renoprotection. Error bars indicate SEM.