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      Urinary Stone Formation: Dent’s Disease Moves Understanding Forward

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          Renal stones form in the late collecting duct in a complex milieu involving salts and protein components of the urine together with direct interactions at the epithelial cells lining the duct. The operation of newly discovered physiological controls that limit crystal formation by feedback mechanisms which sense the luminal environment are discussed. Adhesion at the epithelial surface and intracellular processing of crystals comprise a previously unrecognised mechanism for limiting crystal growth, which may be disrupted resulting in disease. Dent’s disease is discussed as a paradigm of a complex renal tubular disease resulting in renal stone formation. Defects in endosomal acidification, due to ablation of the CLC-5 voltage-gated Cl<sup>–</sup> channel, result in defects in both proximal and collecting duct endosomal traffic leading to stone formation.

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          Most cited references 7

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          X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations.

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            Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl- channel proteins.

            We have cloned and molecularly and functionally characterized the first human member of the family of Ca2+-activated Cl- channels, human (h) CLCA1. The 31,902-bp gene is located on chromosome 1p22-31 and is preceded by a canonic promoter region that contains an L1 transposable element. In contrast to all previously known homologs in other species, hCLCA1 is exclusively expressed in intestinal basal crypt epithelia and goblet cells, suggesting that it does not represent the human counterpart of any of them. Expression of the 914-amino-acid hCLCA1 protein in HEK 293 cells yielded a 125-kDa precursor that was processed to yield two cell-surface-associated subunits, a 90-kDa protein and a group of 37- to 41-kDa proteins. Four transmembrane domains were established within the 90-kDa subunit. HEK 293 cells transfected with CLCA1 exhibited an increase in whole-cell Ca2+-sensitive Cl- currents that were outwardly rectified and inhibited by 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid, dithiothreitol, and niflumic acid. Cell-attached patch recordings of transfected cells revealed single channels with a slope conductance of 13.4 pS. These findings suggest that human CLCA1 mediates a Ca2+-activated Cl- conductance in the human intestine and make it an interesting candidate as a modulating factor in the pathogenesis of cystic fibrosis. Copyright 1998 Academic Press.
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              The extracellular calcium-sensing receptor: its role in health and disease.

              The recent cloning of an extracellular calcium (Ca2+o)-sensing receptor (CaR) from parathyroid, kidney and other cell types has clarified the mechanisms through which Ca2+o exerts its direct actions on various cells and tissues. In the parathyroid, the CaR mediates the inhibitory effects of Ca2+o on parathyroid hormone (PTH) secretion and likely on expression of the PTH gene and parathyroid cellular proliferation. In the kidney, the receptor mediates direct inhibition of the reabsorption of divalent cations in the cortical thick ascending limb, and it likely underlies the inhibitory actions of hypercalcemia on the urinary-concentrating mechanism in the medullary thick ascending limb and inner medullary collecting duct. The identification of inherited diseases of Ca2+o-sensing that arise from mutations in the CaR gene has proven, by genetic means, the central role of the CaR in mineral ion homeostasis and the importance of the receptor in regulating the parathyroid and kidney. An allosteric CaR agonist ("calcimimetic") is currently being tested for the treatment of primary hyperparathyroidism, and CaR-based therapeutics will likely be applicable to other disorders in which CaRs are under- or overactive. Thus the discovery of the CaR and its associated diseases has documented that Ca2+o plays an essential role as an extracellular first messenger, in addition to serving its better recognized role as an intracellular second messenger.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                30 May 2002
                : 10
                : 3
                : 176-181
                Department of Physiological Sciences, University of Newcastle upon Tyne, Newcastle, UK
                58344 Exp Nephrol 2002;10:176–181
                © 2002 S. Karger AG, Basel

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                Figures: 1, References: 26, Pages: 6
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