A mathematical model of potassium homeostasis: Effect of feedforward and feedback controls

Maintaining normal potassium (K+) concentrations in the extra- and intracellular fluid is critical for cell function. K+ homeostasis is achieved by ensuring proper distribution between extra- and intracellular fluid compartments and by matching K+ excretion with intake. The Na+-K+-ATPase pump facilitates K+ uptake into the skeletal muscle, where most K+ is stored. Na+-K+-ATPase activity is stimulated by insulin and aldosterone. The kidneys regulate long term K+ regulation by controlling the amount of K+ excreted through urine. Renal handling of K+ is mediated by a number of regulatory mechanisms, including an aldosterone-mediated feedback control, in which high extracellular K+ concentration stimulates aldosterone secretion which enhances urine K+ excretion, and a gastrointestinal feedforward control mechanism, in which dietary K+ intake increases K+ excretion. Recently, a muscle-kidney cross talk signal has been hypothesized, where the K+ concentration in skeletal muscle cells directly affects urine K+ excretion without changes in extracellular K+ concentration. To understand how these mechanisms coordinate under different K+ challenges, we have developed a compartmental model of whole-body K+ regulation. The model represents the intra- and extracellular fluid compartments in a human (male) as well as a detailed kidney compartment. We included (i) the gastrointestinal feedforward control mechanism, (ii) the effect of insulin and (iii) aldosterone on Na+-K+-ATPase K+ uptake, and (iv) aldosterone stimulation of renal K+ secretion. We used this model to investigate the impact of regulatory mechanisms on K+ homeostasis. Model predictions showed how the regulatory mechanisms synthesize to ensure that the extra- and intracelluller fluid K+ concentrations remain in normal range in times of K+ loading and fasting. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, the model was unable to predict a return to normal extracellular K+ concentration after a period of high K+ loading or depletion. Author summaryPotassium (K+) homeostasis is crucial for normal cell function. Dysregulation of K+ can have dangerous consequences and is a common side effect of pathologies, medications, or changes in hormone levels. Due to its complexities, how the body maintains extra- and intracellular K+ concentrations each day is not fully understood. Of particular interest is capturing how regulatory mechanisms synthesize to be able to keep extracellullar K+ concentration within a tight range of 3.5-5.0 mEq/L. There are a multitude of physiological processes involved in K+ balance, making its study well suited for investigation using mathematical modeling. In this study, we developed a compartment model of extra- and intracellular K+ regulation including the various regulatory mechanisms and a detailed kidney model. The significance of our research is to quantify the effect of individual regulatory mechanisms on K+ regulation as well as predict the potential impact of a hypothesized signal: muscle-kidney cross talk.