Paracrine control of renal function: extracellular nucleotides and sodium reabsorption. (360G-Wellcome-079134_Z_06_Z)

Paracrine control of renal function: extracellular nucleotides and sodium reabsorption Extracellular nucleotides modulate cellular function through interaction with the P2 receptor family. Studies in cell lines have shown that these receptors are powerful regulators of renal sodium transporters and thus can exert a major impact on volume status. Nevertheless, using cell systems to model a complex, highly polarised epithelium compromises meaningful integration into systems physiology; phenotypic delineation of "proximal" and "distal" cell models is not absolute and transporter polarity is often lost in culture. I have demonstrated P2 receptor expression in the rat kidney and performed studies providing evidence for in vivo control of renal sodium transport by ATP. This proposal will extend my initial findings, demonstrating paracrine control of both proximal tubule and collecting duct sodium transport via P2 receptor activation. The application is timely, given that the therapeutic potential of this system has been realised in other epithelia. Moreover, this field represents a clear opportunity for expansion in the future. In order to place myself in a competitive position, this project will also make a novel transgenic mouse carrying a "floxed" allele, allowing targeted deletion of the P2Y1 receptor. This powerful tool will allow dissection of the function of tubule P2Y1 receptors in control of systemic sodium homeostasis.