Thiazide induces hypocalciuria independent of sodium‐calcium exchanger 1

Abstract

Thiazide diuretics are known to decrease renal calcium excretion. The mechanisms and renal segments involved in thiazide‐induced hypocalciuria remain debated. In the distal tubule, thiazide inhibits Na‐Cl cotransporter and may in turn stimulate Na‐Ca exchanger 1 (NCX1) to promote Ca reabsorption. Here, we examined the role of NCX1 in thiazide‐induced hypocalciuria using kidney‐specific NCX1‐knockout (KO) mice. A single dose of 25 mg/kg hydrochlorothiazide (HCTZ) or vehicle was injected to KO and wild‐type (WT) mice and urines were collected 0, 1, 2, 3, and 6 h afterwards. NCX1‐KO and WT mice showed similar diuretic responses to HCTZ with peaks of urinary Na/creatinine within 1 h. HCTZ‐induced hypocalciuria was observed by the decreases in urinary Ca/creatinine at 2 and 3 h after HCTZ and the extent of reduction being greater in KO than in WT at 3 h. Fractional excretion of lithium (FELi) in WT mice was reduced to 30% of baseline level 2 h after HCTZ. Whereas in KO mice, FELi was 3‐ times lower than WT at baseline and was not further reduced after HCTZ. The sustained ability of NCX1‐KO mice to lower Ca excretion after HCTZ indicated minimal roles of NCX1, and probably distal tubule, in thiazide‐induced hypocalciuria. Changes in FELi suggested that proximal tubule and thick ascending limb may be the major contributors for the hypocalciuric effect. Supported by Swiss National Science Foundation and IKPP (FP7) program.