A modeling analysis of whole body potassium regulation on a high-potassium diet: proximal tubule and tubuloglomerular feedback effects.

Potassium (K⁺) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, and hormone secretion and action. Indeed, maintaining K⁺ balance is critical for normal cell function, as too high or too low K⁺ levels can have serious and potentially deadly health consequences. K⁺ homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K⁺ intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na⁺-K⁺-ATPase uptake, and hormone and electrolyte impacts on renal K⁺ handling. We recently developed a mathematical model of whole body K⁺ regulation to unravel the individual impacts of these regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high-K⁺ diet. We conducted model simulations and sensitivity analyses to investigate how these renal alterations impact whole body K⁺ regulation. Model predictions quantify the sensitivity of K⁺ regulation to various levels of proximal tubule K⁺ reabsorption adaptation and tubuloglomerular feedback. Our results suggest that the reduced proximal tubule K⁺ reabsorption under a high-K⁺ diet could achieve K⁺ balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K⁺ excretion.NEW & NOTEWORTHY Potassium homeostasis is maintained in the body by a complex system of regulatory mechanisms. This system, when healthy, maintains a small extracellular potassium concentration, despite large fluctuations of dietary potassium. The complexities of the system make this problem well suited for investigation with mathematical modeling. In this study, we extend our mathematical model to consider recent experimental results on renal potassium handling on a high potassium diet and investigate the impacts from a whole body perspective.