Modeling magnesium and calcium transport along male rat kidney and the effects of diuretics

Calcium (Ca 2+ ) and magnesium (Mg 2+ ) are essential for cellular function. The kidneys play an important role in maintaining the homeostasis of these cations. Their reabsorption along the nephron is dependent on distinct trans- and paracellular pathways, and is coupled to the transport of other electrolytes. Notably, sodium (Na + ) transport establishes an electrochemical gradient to drive Ca 2+ reabsorption. Consequently, alterations in renal Na + handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca 2+ transport. One such condition is the administration of diuretics, which are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. While the pharmacological targets of diuretics typically directly mediate Na + transport, they also indirectly affect renal Ca 2+ and Mg 2+ handling, i.e., by establishing a prerequisite electrochemical gradient. Thus, substantial alterations in divalent cation handling can be expected following diuretic treatment. To investigate renal Ca 2+ and Mg 2 handling, and how those processes are affected by diuretics treatment, we have developed sex-specific computational models of electrolyte transport along the nephrons. Model simulations indicate that along the proximal tubule and thick ascending limb, the transport of Ca 2+ and Mg 2+ occusr in parallel with Na + , but those processes are dissociated along the distal convoluted tubule. We also simulated the effects of acute administration of loop, thiazide, and K-sparing diuretics. The model predicted significantly increased Mg 2+ excretion, no significant alteration in Mg 2+ excretion, and significantly decreased Mg 2+ excretion on treatment with loop, thiazide, and K-sparing diuretics, respectively, in agreement with experimental studies. The present models can be used to conduct in silico studies on how the kidney adapts to alterations in Ca 2+ and Mg 2+ homeostasis during various physiological and pathophysiological conditions, such as pregnancy, diabetes, and chronic kidney disease.