Renal calcium and magnesium handling during pregnancy: modeling and analysis.

Pregnancy is associated with elevated demand of most nutrients, with many trace elements and minerals critical for the development of fetus. In particular, calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function, and their deficiency can lead to impaired fetal growth. A key contributor to the homeostasis of these ions is the kidney, which in a pregnant rat undergoes major changes in morphology, hemodynamics, and molecular structure. The goal of this study is to unravel the functional implications of these pregnancy-induced changes in renal handling of Ca2+ and Mg2+, two cations that are essential in a healthy pregnancy. To achieve that goal, we developed computational models of electrolyte and water transport along the nephrons of a rat in mid and late pregnancy. Model simulations reveal a substantial increase in the reabsorption of Mg2+ along the proximal tubules and thick ascending limbs. In contrast, the reabsorption of Ca2+ is increased in the proximal tubules but decreased in the thick ascending limbs, due to the lower transepithelial concentration gradient of Ca2+ along the latter. Despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of Ca2+ and Mg2+ in pregnancy. Furthermore, we conducted simulations of hypocalcemia and hypomagnesemia. We found that hypocalcemia lowers Ca2+ excretion substantially more than Mg2+ excretion, with this effect being more pronounced in virgin rats than in pregnant ones. Conversely, hypomagnesemia reduces the excretion of Mg2+ and Ca2+ to more similar degrees. These differences can be explained by the greater sensitivity of the calcium-sensing receptor (CaSR) to Ca2+ compared with Mg2+.NEW & NOTEWORTHY A growing fetus' demands of minerals, notably calcium and magnesium, necessitate adaptations in pregnancy. In particular, the kidney undergoes major changes in morphology, hemodynamics, and molecular structure. This computational modeling study provides insights into how these pregnancy-induced renal adaptation impact calcium and magnesium transport along different nephron segments. Model simulations indicate that, despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of calcium and magnesium in pregnancy.

Coupling of renal sodium and calcium transport: a modeling analysis of transporter inhibition and sex differences.

Ca2+ transport along the nephron occurs via specific transcellular and paracellular pathways and is coupled to the transport of other electrolytes. Notably, Na+ transport establishes an electrochemical gradient to drive Ca2+ reabsorption. Hence, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na+ transport but also indirectly affect renal Ca2+ handling. To better understand the underlying mechanisms, we developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca2+ handling are represented. Model simulations predicted in the female rat nephron lower Ca2+ reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared with the male nephron. The male rat kidney model yielded a higher urinary Ca2+ excretion than the female model, consistent with animal experiments. Model results indicated that along the proximal tubule and thick ascending limb, Ca2+ and Na+ transport occurred in parallel, but those processes were dissociated in the distal convoluted tubule. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na+ and Ca2+ transport. Simulation results revealed alterations in transepithelial Ca2+ transport, with differential effects among nephron segments and between the sexes.NEW & NOTEWORTHY The kidney plays an important role in the maintenance of whole body Ca2+ balance by regulating Ca2+ reabsorption and excretion. This computational modeling study provides insights into how Ca2+ transport along the nephron is coupled to Na+. Model results indicated that along the proximal tubule and thick ascending limb, Ca2+ and Na+ transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.

How the kidney regulates magnesium: a modelling study.

The kidneys are crucial for maintaining Mg2+ homeostasis. Along the proximal tubule and thick ascending limb, Mg2+ is reabsorbed paracellularly, while along the distal convoluted tubule (DCT), Mg2+ is reabsorbed transcellularly via transient receptor potential melastatin 6 (TRPM6). TRPM6 and other renal transporter expressions are regulated by sex hormones. To investigate renal Mg2 handling, we have developed sex-specific computational models of electrolyte transport along rat superficial nephron. Model simulations indicated that along the proximal tubule and thick ascending limb, Mg2+ and Na+ transport occur parallelly, but they are dissociated along the DCT. In addition, our models predicted higher paracellular Mg2+ permeability in females to attain similar cortical thick ascending limb fractional Mg2+ reabsorption in both sexes. Furthermore, DCT fractional Mg2+ reabsorption is higher in females than in males, allowing females to better fine-tune Mg2+ excretion. We validated our models by simulating the administration of three classes of diuretics. The model predicted significantly increased, marginally increased and significantly decreased Mg2+ excretions for loop, thiazide and K-sparing diuretics, respectively, aligning with experimental findings. The models can be used to conduct in silico studies on kidney adaptations to Mg2+ homeostasis alterations during conditions such as pregnancy, diabetes and chronic kidney disease.