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Molecular determinants of sodium transport: role of a new aldosterone induced gene


The epithelial Na+ channel (ENaC) plays a major role in the homeostasis of extracellular Na+ and consequently of blood volume and pressure. Its importance is underlined by its genetic linkage to two renal diseases, pseudohypoaldosteronism type I, and of Li ddle¿s syndrome, which are both caused by mutations in the genes encoding ENaC. ENaC, which facilitates entry of Na+ into the cell, is the rate-limiting step of Na+ reabsorption. It is highly regulated by a variety of factors, including aldosterone and vas opressin, but the molecular mechanisms of their action are still poorly understood. Aldosterone induces and/or represses a number of genes, which consequently lead to the stimulation of transepithelial transport. We have identified a novel protein, NDRG2 ( N-myc Downstream Regulated Gene 2) whose expression is very early stimulated by aldosterone, both in established cell lines, and in the kidney and colon of rats. NDRG2 belongs to a family of genes of unknown function, which is conserved in plants, inverteb rates and mammals, suggesting important functions. Its identity with MESK2, a gene recently identified in Drosophila, suggests that it may be involved in the Ras/MAPK signaling pathway. Our preliminary data suggest that aldosterone does influence Ras activ ity, and co-expression of NDRG2 with ENaC into Xenopus laevis oocytes elevates ENaC activity as compared to control oocytes. My project will be focussed on the analysis of NDRG2 function, in cell cultures, and in vivo by transgenesis. We will use condition al systems (tet inducible and HoxB7 promotor kidney-targeting in mice, Tamoxifen-sensitive Cre-Lox in cells) to evaluate the consequences of NDRG2 overexpression on renal collecting duct differentiation, polarity and sodium transport capacities. Constructs have been made, cell transfection is in progress and mouse generation will be initiated in March 2004. We will search for alterations in sodium transport after NDRG2 overexpression.

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