Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney

Kidney Int. 2003 Aug;64(2):555-64. doi: 10.1046/j.1523-1755.2003.00128.x.


Introduction: Thiazide diuretics have the unique characteristic of increasing renal Na+ excretion, while decreasing Ca2+ excretion. However, the molecular mechanism responsible for this thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of thiazides on the expression of the proteins involved in active Ca2+ transport as well as the role of extracellular volume (ECV) status.

Methods: Hydrochlorothiazide (HCTZ), 12 mg/24 hours, was administered during 7 days to Wistar rats by osmotic minipumps. In addition, ECV contraction was either prevented by Na+ repletion or induced by a low-salt diet. Expression levels of the proteins involved in active Ca2+ transport [i.e., epithelial Ca2+ channel (TRPV5/ECaC1), calbindin-D28K, Na+/Ca2+ exchanger (NCX1)], as well as the thiazide-sensitive Na+ Cl- cotransporter (NCC) were determined by real-time quantitative polymerase chain reaction (PCR) and semiquantitative immunohistochemistry.

Results: HCTZ significantly reduced urinary Ca2+ excretion (22%+/- 5% relative to controls). Hematocrit was significantly increased, confirming ECV contraction. In addition, Na+ depletion virtually abolished Ca2+ excretion (8%+/- 1%), while Na+ repletion during HCTZ treatment prevented both ECV contraction and hypocalciuria. HCTZ significantly decreased mRNA expression of TRPV5 (71%+/- 6%), calbindin-D28K (53%+/- 6%), NCX1 (51%+/- 8%) and NCC (50%+/- 11%), regardless of ECV status or calciuresis. Immunohistochemistry revealed reduced TRPV5 (43%+/- 2%), calbindin-D28K (59%+/- 1%) and NCC (56%+/- 4%) abundance. Furthermore, during HCTZ treatment, the subset of tubules coexpressing NCC and calbindin-D28K was significantly reduced (43%+/- 5%) and a disturbed cellular localization of NCC was observed.

Conclusion: These data suggest that ECV contraction is a critical determinant of the thiazide-induced hypocalciuria, which is accompanied by a decreased expression of Ca2+ transport proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / urine*
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism
  • Diuretics
  • Electrolytes / blood
  • Electrolytes / urine
  • Hydrochlorothiazide / pharmacology*
  • Immunoblotting
  • Immunohistochemistry
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Polymerase Chain Reaction
  • Rats
  • Rats, Wistar
  • Sodium / urine
  • Sodium Chloride Symporter Inhibitors / pharmacology*
  • Sodium Chloride Symporters
  • Sodium-Calcium Exchanger / genetics*
  • Sodium-Calcium Exchanger / metabolism
  • Symporters / genetics
  • Symporters / metabolism
  • TRPV Cation Channels


  • Calcium Channels
  • Diuretics
  • Electrolytes
  • Sodium Chloride Symporter Inhibitors
  • Sodium Chloride Symporters
  • Sodium-Calcium Exchanger
  • Symporters
  • TRPV Cation Channels
  • TRPV5 protein, rat
  • sodium-calcium exchanger 1
  • Hydrochlorothiazide
  • Sodium
  • Calcium