Faculté des sciences

Enhanced passive Ca²⁺ reabsorption and reduced Mg²⁺ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia

Nijenhuis, Tom ; Vallon, Volker ; Kemp van der, Annemiete W.C.M. ; Loffing, Johannes ; Hoenderop, Joost G.J. ; Bindels, René J.M.

In: The Journal of Clinical Investigation, 2005, vol. 115(6), p. 1651

Thiazide diuretics enhance renal Na⁺ excretion by blocking the Na⁺-Cl⁻ cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca²⁺ transport in the proximal tubule rather than active Ca²⁺ transport in distal convolution explains... Plus

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    Summary
    Thiazide diuretics enhance renal Na⁺ excretion by blocking the Na⁺-Cl⁻ cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca²⁺ transport in the proximal tubule rather than active Ca²⁺ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na⁺ and Ca²⁺ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca²⁺ reabsorption in distal convolution appeared unaffected. Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5–knockout (Trpv5-knockout) mice, in which active distal Ca²⁺ reabsorption is abolished due to inactivation of the epithelial Ca²⁺ channel Trpv5. Third, HCTZ upregulated the Na⁺/H⁺ exchanger, responsible for the majority of Na⁺ and, consequently, Ca²⁺ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca²⁺ transport was unaltered. Fourth, experiments addressing the time-dependent effect of a single dose of HCTZ showed that the development of hypocalciuria parallels a compensatory increase in Na⁺ reabsorption secondary to an initial natriuresis. Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg²⁺ channel transient receptor potential channel subfamily M, member 6 (Trpm6). Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation.