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lüll Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia Nijenhuis T; Vallon V; van der Kemp AW; Loffing J; Hoenderop JG; Bindels RJJ Clin Invest 2005[Jun]; 115 (6): 1651-8Thiazide 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.|Animals[MESH]|Benzothiadiazines[MESH]|Calcium Channels/genetics/metabolism[MESH]|Calcium Metabolism Disorders/chemically induced/metabolism/pathology[MESH]|Calcium/*metabolism[MESH]|Disease Models, Animal[MESH]|Diuretics[MESH]|Down-Regulation[MESH]|Humans[MESH]|Ion Transport/genetics[MESH]|Kidney Tubules, Proximal/*metabolism/pathology[MESH]|Magnesium/*metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Renal Tubular Transport, Inborn Errors/genetics/*metabolism/pathology[MESH]|Sodium Chloride Symporter Inhibitors/toxicity[MESH]|Sodium-Hydrogen Exchangers/genetics/metabolism[MESH]|Sodium-Potassium-Chloride Symporters/genetics/*metabolism[MESH]|TRPV Cation Channels[MESH]|Up-Regulation[MESH]|Water-Electrolyte Imbalance/chemically induced/*metabolism/pathology[MESH] |