title: Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia.
abstract: 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 Ca2+ transport in the proximal tubule rather than active Ca2+ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na+ and Ca2+ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca2+ 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 Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5. Third, HCTZ upregulated the Na+/H+ exchanger, responsible for the majority of Na+ and, consequently, Ca2+ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca2+ 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 Mg2+ 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.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Nijenhuis
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Annemiete W C M
authors.initials: AW
authors.lastname: van der Kemp
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000818:Animals; D001581:Benzothiadiazines; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002128:Calcium Metabolism Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004232:Diuretics; D015536:Down-Regulation; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008274:Magnesium / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015499:Renal Tubular Transport, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049993:Sodium Chloride Symporter Inhibitors / Q000633:toxicity; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels; D015854:Up-Regulation; D014883:Water-Electrolyte Imbalance / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
chemical_list: D001581:Benzothiadiazines; D015220:Calcium Channels; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D008274:Magnesium; D002118:Calcium