Stadt, M. | Search bioRxiv

bioRxiv2022

Effect of pregnancy and hypertension on kidney function in female rats: Modeling and functional implications

Throughout pregnancy, the kidneys undergo significant adaptations in morphology, hemodynamics, and transport to achieve the volume and electrolyte retention required to support a healthy pregnancy. Additionally, during pregnancies complicated by chronic hypertension, altered renal function from normal pregnancy occurs. The goal of this study is to analyze how inhibition of critical transporters affects gestational kidney function as well as how renal function is affected during chronic hypertension in pregnancy. To do this, we developed epithelial cell-based multi-nephron computational models of solute and water transport in the kidneys of a female rat in mid- and late pregnancy. We simulated the effects of key individual pregnancy-induced changes on renal Na+ and K+ transport: proximal tubule length, Na+/H+ exchanger isoform 3 (NHE3) activity, epithelial Na+ channel activity (ENaC), K+ secretory channel expression, and H+-K+-ATPase activity. Additionally, we conducted simulations to predict the effects of inhibition and knockout of the ENaC and H+-K+-ATPase transporters on virgin and pregnant rat kidneys. Our simulation results predicted that the ENaC and H+-K+-ATPase transporters are essential for sufficient Na+ and K+ reabsorption during pregnancy. Last, we developed models to capture changes made during hypertension in female rats and considered what may occur when a rat with chronic hypertension becomes pregnant. Model simulations predicted that in hypertension for a pregnant rat there is a similar shift in Na+ transport from the proximal tubules to the distal tubules as in a virgin rat.

physiology↗

bioRxiv2022

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.

physiology↗