Effects of Thiazide on the Expression of TRPV5, Calbindin-D_28K, and Sodium Transporters in Hypercalciuric Rats

Abstract

TRPV5 is believed to play an important role in the regulation of urinary calcium excretion. We assessed the effects of hydrochlorothiazide (HCTZ) on the expression of TRPV5, calbindin-D28K, and several sodium transporters in hypercalciuric rats. Sprague-Dawley rats were divided into 4 groups; control, HCTZ, high salt, and high salt with HCTZ group in experiment 1; control, HCTZ, high calcium (Ca), and high Ca with HCTZ group in experiment 2. To quantitate the expression of TRPV5, calbindin-D28K, and sodium transporters, western blotting was performed. In both experiments, HCTZ significantly decreased urinary calcium excretion. TRPV5 protein abundance decreased in all hypercalciuric rats, and restored by HCTZ in both high salt with HCTZ and high Ca with HCTZ group. Calbindin-D28K protein abundance increased in the high salt and high salt with HCTZ groups, but did not differ among groups in experiment 2. Protein abundance of NHE3 and NKCC2 decreased in all hypercalciuric rats, and were restored by HCTZ in only high Ca-induced hypercalciuric rats. In summary, protein abundance of TRPV5, NHE3, and NKCC2 decreased in all hypercalciuric rats. The hypocalciuric effect of HCTZ is associated with increased protein abundance of TRPV5 in high salt or calcium diet-induced hypercalciuric rats.

Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome

“…Next, we measured the protein abundance of NCC, which is sensitive to thiazide and responsible for reabsorption of 5-10% of filtered sodium in the distal convoluted tubules [38]. Several studies have suggested that treatment with HCTZ [39][40][41] or furosemide [38,40] significantly increases the protein abundance of NCC in renal cortical tissues, an effect that might be induced by compensatory effects against increases in sodium and water load at distal nephrons. Interestingly, luseogliflozin alone also showed similar increases in expression of NCC protein.…”

Insight on the Mechanism of the Effects of Hydrochlorothiazide on Nocturnal Enuresis

“…Recently, it was suggested that transient receptor potential vanilloid 5 (TRPV5) detected in renal distal convoluted tubule might play an important role in the regulation of urinary calcium excretion [3] . The downregulation of TRPV5 decreased urine calcium reabsorption and led to loss of the urine calcium, resulting in hypercalciuria [4] .…”

“…The downregulation of TRPV5 decreased urine calcium reabsorption and led to loss of the urine calcium, resulting in hypercalciuria [4] . Furthermore, Jang et al [3] recently showed that the hypocalciu- wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. …”

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

“…However, TZ can prevent (23) or significantly blunt (17) the rise in Ca excretion seen when rodents receive sodium supplementation to prevent volume depletion during TZ administration, and upregulation of distal tubule Ca channel (TRPV5) and calbindin expression has been reported with administration of TZ in some (17, 23), but not all (27), studies. These data suggest that increased distal nephron Ca reabsorption may be an important mechanism for TZinduced hypocalciuria in some circumstances (17,23).We set out to determine the mechanism by which chronic TZ administration leads to decreased urine Ca excretion in human stone formers with IH; if increased proximal tubule sodium and Ca reabsorption is at least some component of this phenomenon, then in addition to lowering the recurrence of stones, decreased Randall's plaque formation could be a second benefit of TZ treatment. …”

“…However, TZ can prevent (23) or significantly blunt (17) the rise in Ca excretion seen when rodents receive sodium supplementation to prevent volume depletion during TZ administration, and upregulation of distal tubule Ca channel (TRPV5) and calbindin expression has been reported with administration of TZ in some (17,23), but not all (27), studies. These data suggest that increased distal nephron Ca reabsorption may be an important mechanism for TZinduced hypocalciuria in some circumstances (17,23).…”