¹Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, Hamburg, Germany

Correspondence: TJ Jentsch, Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, Falkenried 94, Hamburg D-20252, Germany. E-mail: Jentsch@zmnh.uni-hamburg.de

²These authors contributed equally to this work

Received 23 June 2005; Revised 17 January 2006; Accepted 10 February 2006; Published online 3 May 2006.

Abstract

Mutations in ClC-5 cause Dent's disease, a disorder associated with low molecular weight proteinuria, hyperphosphaturia, and kidney stones. ClC-5 is a Cl^-/H⁺-exchanger predominantly expressed in the kidney, where it facilitates the acidification of proximal tubular endosomes. The reduction in proximal tubular endocytosis resulting from a lack of ClC-5 raises the luminal concentration of filtered proteins and peptides like parathyroid hormone (PTH). The increase in PTH may explain the hyperphosphaturia observed in Dent's disease. Expression profiling, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and hormone measurements were used to investigate whether the disruption of ClC-5 affects other signalling pathways. Although the upregulation of 25(OH)₂-vitamin D₃ 1-hydroxylase and downregulation of vitamin D₃ 24-hydroxylase suggested an increased formation of 1,25(OH)₂-vitamin D₃, the concentration of this active metabolite was reduced in the serum of ClC-5 knockout (KO) mice. However, target genes of 1,25(OH)₂-vitamin D₃ were upregulated in KO kidneys. Expression analysis of intestine and bone revealed that the upregulation of 1,25(OH)₂-vitamin D₃ target genes was kidney intrinsic and not systemic. In spite of reduced serum levels of 1,25(OH)₂-vitamin D₃ in ClC-5 KO mice, 1,25(OH)₂-vitamin D₃ is increased in later nephron segments as a consequence of impaired proximal tubular endocytosis. This leads to a kidney-specific stimulation of 1,25(OH)₂-vitamin D₃ target genes that may contribute to the pathogenesis of Dent's disease. The activation of genes in distal nephron segments by hormones that are normally endocytosed in the proximal tubule may extend to other pathways like those activated by retinoic acid.