Kir5.1-modulated potassium flux stimulates an anabolic kidney phenotype

The kidney maintains systemic potassium (K⁺) balance through energy-intensive epithelial transport processes. Under K⁺-restricted conditions, kidney epithelial cells proliferate to accommodate profound increases in transport. Tissue reorganization to minimize systemic K⁺ loss is essential for survival, yet metabolic details remain obscure. Here, we demonstrate that the most-activated kidney pathways under low K⁺ conditions are those governing metabolism, including carbohydrate- and glutamine-based processes and fatty acid synthesis. We identify that reduced K⁺ intake stimulates glycolytic flux in the renal cortex to increase amino acid abundance, <i>de novo</i> fatty acid synthesis, and organ expansion. Using a novel mouse model harboring a dominant-negative K_ir5.1 channel, we show that each of these steps is dependent on intact basolateral K_ir channel flux to initiate rapid kidney growth. Results identify details of a low K⁺-simulated anabolic kidney program requiring K_ir channel function and highlight a therapeutic role for targeting K_ir channels to modulate cell physiology and metabolism.