Sphingosylphosphorylcholine and its contribution to pathophysiological processes in the kidney

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Sphingosylphosphorylcholine (SPC) shows structural similarities to both sphingosine 1- phosphate (S1P) and lysophosphatidylcholine (LPC), and is similarly able to bind to a subset of G protein-coupled receptors (GPCRs) to finally trigger responses such as cell proliferation, vessel contraction or dilatation, and modulation of inflammatory and fibrotic processes. This project aims in identifying the involved SPC receptors that contribute to an anti-inflammatory and pro-fibrotic response of renal cells. A special focus will be put on the crosstalk between GPCRs binding sphingolipids and receptors with serine/threonine kinase activity like the TGFβ receptor, thus highlighting an additional pathophysiologically relevant facet of GPCR-triggered receptor transmodulation. Starting from the known effects of TGFβ on fibrotic processes we will investigate the role of sphingolipid-triggered signal transduction on matrixregulating enzymes, such as matrix metalloproteinase-9, tissue plasminogen activataor (tPA) and their endogenous inhibitors TIMPs and PAIs. Furthermore, we plan to characterize the generation of SPC during physiological and pathophysiological conditions in the kidney and to identify the relevant SPC receptors. On a long-term basis GPCRs specific for sphingolipids (SPC and S1P receptors) will be investigated as potential pharmacological targets to treat fibrotic renal diseases.