Effect of diuretics on renal tubular transport of calcium and magnesium

Calcium (Ca2+) and Magnesium (Mg2+) reabsorption along the renal tubule is dependent on distinct trans-and paracellular pathways. Our understanding of the molecular machinery involved is increasing. Ca(2+)and Mg2+ reclamation in kidney is dependent on a diverse array of proteins, which are important for both forming divalent cation-permeable pores and channels, but also for generating the necessary driving forces for Ca(2+)and Mg2+ transport. Alterations in these molecular constituents can have profound effects on tubular Ca(2+)and Mg2+ handling. Diuretics are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate sodium (Na+) transport, but also indirectly affect renal Ca2+ and Mg2+ handling, i.e., by establishing a prerequisite electrochemical gradient. It is therefore not surprising that substantial alterations in divalent cation handling can be observed following diuretic treatment. The effects of diuretics on renal Ca2+ and Mg2+ handling are reviewed in the context of the present understanding of basal molecular mechanisms of Ca2+ and Mg2+ transport. Acetazolamide, osmotic diuretics, Na+/H+ exchanger (NHE3) inhibitors, and antidiabetic Na+/glucose cotransporter type 2 (SGLT) blocking compounds, target the proximal tubule, where paracellular Ca2+ transport predominates. Loop diuretics and renal outer medullary K+(ROMK) inhibitors block thick ascending limb transport, a segment with significant paracellular Ca2+ and Mg2+ transport. Thiazides target the distal convoluted tubule; however, their effect on divalent cation transport is not limited to that segment. Finally, potassium-sparing diuretics, which inhibit electrogenic Na+ transport at distal sites, can also affect divalent cation transport.