Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression.
Dent's disease is an X-linked inherited disorder characterized by hypercalciuria, nephrocalcinosis, nephrolithiasis, low molecular weight proteinuria, Fanconi's syndrome, and renal failure. It is caused by inactivating mutations in CLC5, a member of the CLC voltage-gated chloride channel family. CLC5 is known to be expressed in the endosomal compartment of the renal proximal tubule, where it may be required for endosomal acidification and trafficking. Although the Fanconi's syndrome and low molecular weight proteinuria in Dent's disease can be explained by disruption of endosomal function in this nephron segment, the pathogenesis of the hypercalciuria in this disease is unknown. We have generated transgenic mice (RZ) with reduced CLC5 expression by introduction of an antisense ribozyme targeted against CLC5. RZ mice are markedly hypercalciuric compared with nontransgenic control mice, at a time when their serum electrolytes and renal function are otherwise normal. This suggests that hypercalciuria in Dent's disease is a direct consequence of CLC5 hypofunction and is not attributable to a gain of function by mutant CLC5, an effect of modifier genes, or a secondary result of nonspecific renal injury. Surprisingly, hypercalciuria in RZ mice is abolished by dietary calcium deprivation, suggesting that the hypercalciuria may be attributable to gastrointestinal hyperabsorption of calcium rather than a renal calcium leak.
Luyckx
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VA
Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Leclercq
B
B
Dowland
L K
LK
Yu
A S
AS
D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D002118:Calcium / Q000378:metabolism / Q000652:urine*; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D004032:Diet; D004573:Electrolytes / Q000097:blood; D005260:Female; D005838:Genotype; D007668:Kidney / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010641:Phenotype; D016337:RNA, Catalytic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D012737:Sex Factors
C097503:CLC-5 chloride channel; D018118:Chloride Channels; D004573:Electrolytes; D016337:RNA, Catalytic; D002118:Calcium