Toxicity of the kidney proximal tubule by cadmium-metallothionein: Role of lipocalin-2 receptor-mediated endocytosis, vesicle trafficking and lysosomal DMT1

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Chronic exposure to the environmental contaminant cadmium (Cd) damages the kidney proximal tubule (PT). In the body Cd is bound to the protein metallothionein (MT), which is filtrated from the blood and reabsorbed by the PT to induce renal damage. In previous studies, we have shown using cultured PT cells that CdMT uptake and toxicity involves receptor-mediated endocytosis (RME), which is partly mediated by megalin and cubilin. The small GTPase ARF6 regulates early endosomal trafficking of CdMT and receptor recycling to the cell surface. The divalent metal transporter DMT1 is expressed in lysosomes of PT and participates in CdMT toxicity. Using cultured PT cells and megalinor DMT1-knockout animal models in vivo, the role of an additional receptor, the lipocalin-2 receptor, will be investigated in PT cells for RME of CdMT. Furthermore, the significance of the regulatory protein ARF1 for trafficking of CdMT from endosomes to lysosomes will be studied and degradation mechanisms of the CdMT complex will be characterized. Finally, membrane processes will be determined that are responsible for DMT1-mediated Cd fluxes from lysosomes to target organelles of Cd-toxicity (particularly mitochondria). Elucidation of these mechanisms may lead to rationales and strategies for prevention and therapy of Cd-toxicity.