| First Author | Nijenhuis T | Year | 2005 |
| Journal | J Clin Invest | Volume | 115 |
| Issue | 6 | Pages | 1651-8 |
| PubMed ID | 15902302 | Mgi Jnum | J:99204 |
| Mgi Id | MGI:3581474 | Doi | 10.1172/JCI24134 |
| Citation | Nijenhuis T, et al. (2005) Enhanced passive Ca(2+) reabsorption and reduced Mg(2+) channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 115(6):1651-1658 |
| abstractText | 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 Ca(2+) transport in the proximal tubule rather than active Ca(2+) transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na(+) and Ca(2+) in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca(2+) 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 Ca(2+) reabsorption is abolished due to inactivation of the epithelial Ca(2+) channel Trpv5. Third, HCTZ upregulated the Na(+)/H(+) exchanger, responsible for the majority of Na(+) and, consequently, Ca(2+) reabsorption in the proximal tubule, while the expression of proteins involved in active Ca(2+) 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 Mg(2+) 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. |
