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

J Clin Invest. 2005 Jun;115(6):1651-8. doi: 10.1172/JCI24134. Epub 2005 May 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiadiazines
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Metabolism Disorders / chemically induced
  • Calcium Metabolism Disorders / metabolism
  • Calcium Metabolism Disorders / pathology
  • Disease Models, Animal
  • Diuretics
  • Down-Regulation
  • Humans
  • Ion Transport / genetics
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Magnesium / metabolism*
  • Mice
  • Mice, Knockout
  • Renal Tubular Transport, Inborn Errors / genetics
  • Renal Tubular Transport, Inborn Errors / metabolism*
  • Renal Tubular Transport, Inborn Errors / pathology
  • Sodium Chloride Symporter Inhibitors / toxicity
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism
  • Sodium-Potassium-Chloride Symporters / genetics
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • TRPV Cation Channels
  • Up-Regulation
  • Water-Electrolyte Imbalance / chemically induced
  • Water-Electrolyte Imbalance / metabolism*
  • Water-Electrolyte Imbalance / pathology


  • Benzothiadiazines
  • Calcium Channels
  • Diuretics
  • Sodium Chloride Symporter Inhibitors
  • Sodium-Hydrogen Exchangers
  • Sodium-Potassium-Chloride Symporters
  • TRPV Cation Channels
  • Trpv5 protein, mouse
  • Magnesium
  • Calcium