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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/F732    most recent 00121.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Font-Llitjós, M. Articles by Nunes, V. Search for Related Content PubMed PubMed Citation Articles by Font-Llitjós, M. Articles by Nunes, V.

Slc7a9 knockout mouse is a good cystinuria model for antilithiasic pharmacological studies

¹Medical and Molecular Genetics Center, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat; ²Genetic Unit, Department of Physiology II, Universitat de Barcelona-IDIBELL; ³Centre for Biomedical Research on Rare Diseases (CIBERER-U730); and ⁴Epidemiology and Cancer Registry Unit, ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona; ⁵Molecular Nutrition Unit, Technical Univeristy of Munich, Freising, Germany; and ⁶Animal Facility Service, IRO-IDIBELL, L'Hospitalet de Llobregat; ⁷Department of Biochemistry and Molecular Biology, Universitat de Barcelona; ⁸Parc Científic de Barcelona; and ⁹CIBERER-U731, Barcelona, Spain

Submitted 13 March 2007 ; accepted in final form 15 June 2007

Cystinuria is a hereditary disorder caused by a defect in the apical membrane transport system for cystine and dibasic amino acids in renal proximal tubules and intestine, resulting in recurrent urolithiasis. Mutations in SLC3A1 and SLC7A9 genes, that codify for rBAT/b^0,+AT transporter subunits, cause type A and B cystinuria, respectively. In humans, cystinuria treatment is based on the prevention of calculi formation and its dissolution or breakage. Persistent calculi are treated with thiols [i.e., D-penicillamine (DP) and mercaptopropionylglycine (MPG)] for cystine solubilization. We have developed a new protocol with DP to validate our Slc7a9 knockout mouse model for the study of the therapeutic effect of drugs in the treatment of cystine lithiasis. We performed a 5-wk treatment of individually caged lithiasic mutant mice with a previously tested DP dose. To appraise the evolution of lithiasis throughout the treatment a noninvasive indirect method of calculi quantification was developed: calculi mass was quantified by densitometry of X-ray images from cystinuric mice before and after treatment. Urine was collected in metabolic cage experiments to quantify amino acids in DP-treated and nontreated, nonlithiasic mutant mice. We found significant differences between DP-treated and nontreated knockout mice in calculi size and in urinary cystine excretion. Histopathological analysis showed that globally nontreated mutant mice had more severe and diffuse urinary system damage than DP-treated mice. Our results validate the use of this mouse model for testing the efficacy of potential new drugs against cystinuria.

D-Penicillamine treatment; cystinuria model; calculi; noninvasive imaging system