Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b(0,+) AT (Slc7a9) in mice

作者：Di Giacopo Andrea; Rubio Aliaga Isabel; Cantone Alessandra; Artunc Ferruh; Rexhepaj Rexhep; Frey Wagner Isabelle; Font Llitjos Mariona; Gehring Nicole; Stange Gerti; Jaenecke Isabel; Mohebbi Nilufar; Closs Ellen I; Palacin Manuel; Nunes Virginia; Daniel Hannelore; Lang Florian; Capasso Giovambattista; Wagner Carsten A^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2013, 305(12): F1645-F1655.

DOI：10.1152/ajprenal.00221.2013

• cystinuria
• GFR
• peptide transporter
• SLC7A9
• cystine

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+) AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (similar to 100%), but fractional excretions of lysine (similar to 35%), ornithine (similar to 16%), and cystine (similar to 11%) were less affected. Loss of function of b(0,+) AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

• 出版日期2013-12