Project 8 - Dysfunction in epithelial sodium transport under proteinuric conditions

Project Summary

Changes of tubular sodium reabsorption play an important role in the maintenance of volume homeostasis under physiological conditions. In proteinuric states however, defective sodium balance likely contributes to accompanied clinical evident sequelaes like edema and hypertension. The underlying mechanisms as well as the responsible nephron segment and transport mechanism needs to be clarified. We test the hypothesis that proteinuria leads to changes in epithelial transporters and channels which favour to subsequent volume retention. We aspire to identify possible variations in sorting and expression of tubular membrane proteins. Therefore proteinuric rat models of anti-Thy1-glomerulonephritis (Thy1-GN), and puromycin-induced nephritis, and a mouse model of anti-glomerular basement membrane nephritis (GBM-GN) will be evaluated with biochemical and histochemical methods. In Thy1-GN, nephron segment specific changes in expression and localisation of epithelial transporters and channels, concentration of systemic parameters of the renin-angiotensin-system and vasopressin will be evaluated. GBM-GN induced in megalin transgenic mice will clarify the role of increased proximal tubular protein endocytosis on expression and activity of proximal tubular transporters and channels. Mechanisms of activation and deactivation of transporters and channels, participating cell compartment specific proteins, and the role of lipid composition under proteinuria will be characterized. The anticipated results will provide a comprehensive analysis of the cell biological basis underlying the clinical important consequences of nephron epithelial shuttling and transport in proteinuric diseases.

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