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

Abstract

Potassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, as well as 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 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 unravel how these renal alterations impact whole-body K+ regulation. 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. Model predictions quantify the sensitivity of K+ regulation to various levels of proximal tubule K+ reabsorption adaptation and tubuloglomerular feedback. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, intracellular K+ stores can exceed normal range under a high K+ diet.