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Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney Nijenhuis T; Hoenderop JG; Loffing J; van der Kemp AW; van Os CH; Bindels RJKidney Int 2003[Aug]; 64 (2): 555-64INTRODUCTION: 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.|Animals[MESH]|Calcium Channels/*genetics/metabolism[MESH]|Calcium/*urine[MESH]|Diuretics[MESH]|Electrolytes/blood/urine[MESH]|Hydrochlorothiazide/*pharmacology[MESH]|Immunoblotting[MESH]|Immunohistochemistry[MESH]|Kidney/drug effects/metabolism[MESH]|Male[MESH]|Polymerase Chain Reaction[MESH]|Rats[MESH]|Rats, Wistar[MESH]|Sodium Chloride Symporter Inhibitors/*pharmacology[MESH]|Sodium Chloride Symporters[MESH]|Sodium-Calcium Exchanger/*genetics/metabolism[MESH]|Sodium/urine[MESH]|Symporters/genetics/metabolism[MESH]|TRPV Cation Channels[MESH] |
