Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the primary urine and release to the blood. These cells are equipped on their apical and basal membrane with copper transporters CTR1 and ATP7A. Mosaic mutant mice displaying a functional dysfunction of ATP7A are an established model of Menkes disease. These mice exhibit systemic copper deficiency despite renal copper overload, enhanced by copper therapy, which is indispensable for their life span extension. The aim of this study was to analyze the expression of Slc31a1 and Slc31a2 genes (encoding CTR1/CTR2 proteins) and the cellular localization of the CTR1 protein in suckling, young and adult mosaic mutants. Our results indicate that in the kidney of both intact and copper-injected 14-day-old mutants showing high renal copper content, CTR1 mRNA level is not up-regulated compared to wild-type mice given a copper injection. The expression of the Slc31a1 gene in 45-day-old mice is even reduced compared with intact wild-type animals. In suckling and young copper-injected mutants, the CTR1 protein is relocalized from the apical membrane to the cytoplasm of epithelial cells of proximal tubules, the process which prevents copper transport from the primary urine and, thus, protects cells against copper toxicity.
Copper Transporter 1 , Copper , Epithelial Cells , Kidney Tubules, Proximal , Menkes Kinky Hair Syndrome , Animals , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Cell Membrane/genetics , Cell Membrane/metabolism , Copper/metabolism , Copper/toxicity , Copper Transporter 1/genetics , Copper Transporter 1/metabolism , Copper-Transporting ATPases/genetics , Copper-Transporting ATPases/metabolism , Cytoplasm/genetics , Cytoplasm/metabolism , Disease Models, Animal , Epithelial Cells/metabolism , Gene Expression , Kidney Tubules, Proximal/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Menkes Kinky Hair Syndrome/etiology , Menkes Kinky Hair Syndrome/genetics , Menkes Kinky Hair Syndrome/metabolism , Mice , Protein Transport/genetics , Protein Transport/physiology , RNA, Messenger/metabolism , SLC31 Proteins/genetics , SLC31 Proteins/metabolism
