Normal pregnancy is characterized by massive increases in plasma volume and electrolyte retention. Given that the kidneys regulate homeostasis of electrolytes and volume, the organ undergoes major adaptations in morphology, hemodynamics, and transport to achieve the volume and electrolyte retention required in pregnancy. These adaptations are complex, sometimes counterintuitive, and not fully understood. In addition, the demands of the developing fetus and placenta change throughout the pregnancy. For example, during late pregnancy, K+ retention and thus enhanced renal K+ reabsorption is required despite many kaliuretic factors. The goal of this study is to unravel how known adaptive changes along the nephrons contribute to the ability of the kidney to meet volume and electrolyte requirements in mid- and late pregnancy. We developed computational models of solute and water transport in the superficial nephron of the kidney of a rat in mid- and late pregnancy. The mid-pregnant and late-pregnant rat superficial nephron models predict that morphological adaptations and increased activity of the sodium hydrogen exchanger 3 (NHE3) and epithelial sodium channel (ENaC) are essential for enhanced Na+ reabsorption observed during pregnancy. Model simulations showed that for sufficient K+ reabsorption, increased H +-K +-ATPase activity and decreased K+ secretion along the distal segments is required in both mid- and late-pregnancy. Furthermore, certain known sex differences in renal transporter pattern (e.g., the higher NHE3 protein abundance but lower activity in the proximal tubules of virgin female rats compared to male) may serve to better prepare the female for the increased transport demand in pregnancy.
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+ homeostasis 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.
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