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

Abstract

Calcium (Ca2+) and magnesium (Mg2+) 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 Ca2+ reabsorption. Consequently, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ 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 Ca2+ and Mg2+ 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 Ca2+ and Mg2 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 Ca2+ and Mg2+ 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 Mg2+ excretion, no significant alteration in Mg2+ excretion, and significantly decreased Mg2+ 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 Ca2+ and Mg2+ homeostasis during various physiological and pathophysiological conditions, such as pregnancy, diabetes, and chronic kidney disease.