Abstract
Background:
Potassium intake is strongly associated with cardiometabolic health, yet the mechanisms linking electrolyte balance to systemic metabolism remain poorly defined. We hypothesized that renal epithelial AKT acts as a potassium-responsive signaling node that coordinates potassium homeostasis and metabolic adaptation.
Methods:
Inducible nephron-wide and proximal tubule-specific AKT1/AKT2 knockout mice were generated to define the role of epithelial AKT in renal potassium handling and metabolism. Physiologic, molecular, proteomic, and metabolic analyses were performed under normal and potassium-restricted dietary conditions, complemented by mechanistic studies in cultured cells.
Results:
Proteomic analysis revealed that dietary potassium restriction stimulated AKT-dependent pathways in the kidney, including glycolysis and de novo lipogenesis. Nephron-wide and proximal tubule-specific AKT deletion impaired adaptation to potassium deprivation, resulting in urinary potassium wasting, reduced kidney hypertrophy, diminished proximal tubule transporter expression, and hypokalemia. Mechanistically, AKT loss suppressed low-K
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-induced glycolytic and lipogenic programs, reduced de novo palmitate synthesis, and promoted a renal catabolic, ketogenic phenotype characterized by increased HMGCS2 expression and ketone production. In vitro studies showed that low-potassium-induced AKT activation required mTOR activity but was independent of Rictor, whereas Sin1 and mLST8 were essential. AKT deletion also reduced expression of the proximal tubule glucose transporters SGLT1 and SGLT2, causing glycosuria. These renal adaptations were accompanied by lower fasting glucose levels, improved glucose tolerance, enhanced insulin sensitivity, and increased AKT signaling in liver and skeletal muscle.
Conclusions:
Renal epithelial AKT was required for adaptation to dietary potassium restriction. AKT deletion impaired potassium conservation, reduced kidney growth and proximal tubular transport function, and promoted a shift from anabolic to catabolic renal metabolism. These changes were accompanied by glycosuria and systemic metabolic alterations, including lower fasting glucose levels, improved glucose tolerance, and enhanced insulin sensitivity.