Signalling of excretory transport proteins in the kidney

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Man and Animal are exposed to many environmental toxins (heavy metals, pesticides), which also influence metabolism and transport proteins. Our recent studies show that also ABC-exportpumps (P-Glycoprotein, Bcrp, Mrp2, Mrp4,) are modified in their function and expression. The model spezies Killifish (Fundulus heteroclitus) expresses in proximal kidney tubules these transporters, which are very similar to those found in man. We studied function and Signalling cascades of these transporters, e.g. influence of Cadmium- and Mercury- salts. These salts resulted in a reduced transporter function. Preliminary experiments show that Zinc-salts have exactly the opposite effect - increased function of ABC transporters in Killifish tubules. Here , we want to clarify the signalling cascade. First studies suggest and initial Ca2+ influx into tubular cells, triggering a signal cascade via the Endothelinrezeptor B, NO-Synthase, Proteinkinase C, Sphingosinkinase, Sphingosinkinasereceptor, Phosphatidylinositid-3-Kinase, Akt, until mTOR. By kinetic experiments with specific fluorescent substrates of the ABC-transporters and use of modulators of the single components of this signalling pathway (agonists(antagonists, inhibitors) we aim to verify our assumptions. These experiments will be performed in summer 2016 during 4 weeks at the Mount Desert Island Biological Laboratory, Maine, USA. Furtheron, it is planned by Western-Blot and PCR to study , geprüft werden, whether long term Zn²+-Exposition of the tubuli also results in an increased expression of the transporters.