How the kidney regulates magnesium: a modelling study.

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