Decreased Expression of the Slc31a1 Gene and Cytoplasmic Relocalization of Membrane CTR1 Protein in Renal Epithelial Cells: A Potent Protective Mechanism against Copper Nephrotoxicity in a Mouse Model of Menkes Disease

• Published in: International journal of molecular sciences Vol. 23; no. 19; p. 11441
• Main Authors: Haberkiewicz, Olga, Lipiński, Paweł, Starzyński, Rafał R., Jończy, Aneta, Kurowska, Patrycja, Ogórek, Mateusz, Bednarz, Aleksandra, Herman, Sylwia, Hatala, Dawid, Grzmil, Paweł, Rajfur, Zenon, Baster, Zbigniew, Lenartowicz, Małgorzata
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 28-09-2022; MDPI
• Subjects: Age groups; Copper; CTR1 protein; Cytoplasm; Enzymes; Epithelial cells; Epithelium; Gene expression; Homeostasis; Investigations; kidney; Kidneys; Life span; Liver; Localization; Mammals; Membrane proteins; Membranes; Menkes disease; Menkes syndrome; Metabolism; Mosaics; mRNA; Mutants; Mutation; Physiology; Proteins; Proximal tubules; Slc31a1 gene; Slc31a2 gene; Small intestine; Suckling behavior; Toxicity; Urine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911441

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.