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Biomedical implications of epithelial transporters and channels

Final Activity Report Summary - TRANSCURE (Biomedical implications of epithelial transporters and channels)

Kidney stone disease is a major health problem worldwide, with a lifetime incidence of 10%. Genetic factors appear to be involved since 40% of these patients have a positive family history. Idiopathic hypercalciuria is the most common abnormality observed in calcium stone formers. The intestinal and renal epithelial Ca2+ transport mechanisms are comprised of three steps: (i) apical Ca2+ entry via TRPV-calcium channels (transient receptor potential channels, subtype V), which is likely to be a rate-limiting step of transepithelial calcium transport; (ii) binding of Ca2+ to calbindin D which serves as an intracellular Ca2+ buffer, and (iii) basolateral calcium exit via the plasma membrane Ca2+ pump and/or the Na+/ Ca2+ exchanger. Steps 1 and 2 are induced by 1,25-dihydroxyvitamin D, the active form of vitamin D. The key molecules for the apical Ca2+ entry, TRPV5 and TRPV6, were previously identified by expression cloning from the kidney and small intestine, respectively. trpv5 knockout mice exhibited renal leak hypercalciuria with increased intestinal Ca2+ absorption due to a compensatory upregulation of trpv6. In humans, however, no phenotype-genotype relationship between TRPV5 polymorphisms and hypercalciuria has been observed so far, possibly due to this compensation.

On the other hand, trpv6 knockout mice exhibited decreased intestinal Ca2+ absorption without obvious compensation by trpv5 in the intestine, resulting in secondary hyperparathyroidism. In our studies, we investigated the coding region of the TRPV6 gene in 170 Swiss Ca2+ stone formers. We found a haplotype containing three non-synonymous polymorphisms. Our functional analyses demonstrate that it produces a gain-of-function channel. Our results strongly indicate that genetic alterations of the TRPV6 gene are risk factors for hypercalciuria. The outcome of these proposed studies may help decrease the cost of medical treatment of kidney stone patients through the development of more specific treatment approaches that are based on knowledge of our TRPV and also citrate transporter molecules.