Slc7a9knockout mouse is a good cystinuria model for antilithiasic pharmacological studies

Abstract

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,ϩ 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.

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

“…We show that the mRNA expression level of most luminal transporters is equal along the small intestine (duodenum (parts II and III) and terminal ileum) with the exception of the cysteine and dibasic AA exchanger subunit b 0,+ AT. Together with the glycoprotein rBAT, this catalytic subunit forms a heteromeric AA exchanger composed of two subunits covalently linked together (Chillaron et al 2010;Font-Llitjos et al 2007). In murine intestine, both transporter subunits were shown to be expressed at a higher level in ileum than in jejunum and duodenum (Dave et al 2004).…”

Aminoacidurias: Clinical and molecular aspects

“…27 As in humans, oral treatment of this mouse model with D-penicillamine reduced the size and number of calculi. 28 …”

Cystinuria—a urologist's perspective

“…6,68,69 These mouse models and advances in the propagation of cystine crystals have led to the testing of cystine dimethyl ester (CDME), a cystine analo gue that disrupts cystine crystal formation by attaching to their surfaces. CDME can reduce stone mass and size in mice but has not yet been tested in clinical trials.…”