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Since the ALK Inhibitor buildings of sphinganine 1 phosphate and S1P are similar, we postulated that sphinganine 1 phosphate functioning on the cell surface S1P receptors may mediate hepatic and renal protection after liver IR. Protective effects of S1P receptor signaling to protect against liver and kidney injury have been demonstrated previously in vivo. As an example, FTY720 protected against liver IR in subjects possibly via activation of S1P receptor modulation. More over, many S1P receptor agonists, including FTY 720, S1P and SEW 2871, protected against renal IR damage in vivo via reducing renal proximal tubule influx of T lymphocytes with subsequent reduction in necrosis and inflammation. We show in this study that sphinganine 1 phosphate mediated kidney and liver safety after liver IR is S1P1 receptor mediated as a selective S1P1 receptor antagonist blocked the protective effects of sphinganine 1 phosphate. S1P3 antagonists and selective S1P2 had no influence on sphinganine 1 phosphate mediated liver and kidney safety after liver IR. All Inguinal canal of these antagonists for S1P receptors provide extreme selectivity for their respective receptor subtypes. To further measure the role of S1P1 receptors in sphinganine 1 phosphate mediated liver and kidney protection, we utilized siRNA targeting S1P1 receptors in mice in vivo to fit the data acquired with pharmacological inhibitor studies. We were able to uniquely down-regulate S1P1 receptors in adult mice with siSTABLE constructs in vivo which triggered total loss of sphinganine 1 phosphate mediated hepatic and renal defense after liver IR. We also show in this study that sphinganine 1 phosphate via S1P1 receptor activation leads to phosphorylation of Akt, ERK MAPK and HSP27 as well as induction of HSP27 in mouse kidney and liver as well as cultured human renal endothelial cells. Endothelial selectivity is suggested as sphinganine 1 phosphate failed to phosphorylate Akt, GW0742 ERK MAPK and HSP27 in human kidney proximal tubule epithelial cell line. The differential molecular mechanisms for these signaling differences between proximal tubules cells and endothelial cells remain to be elucidated. Activation of ERK MAPK is clearly connected with improved protection against many types of damage including necrosis and apoptosis. The serine/threonine kinase Akt can be an crucial part of cell survival pathways in lots of cell types. Specifically, Akt has various functions to counter-act apoptosis including phosphorylation of several professional apoptotic factors and inhibition of mitochondrial cytochrome c. HSP27 is a member of family of chaperone proteins that are up regulated in response to a wide selection of cellular stresses including ischemia, hypoxia and exposure to hazardous drugs. Increased expression of HSP27 serves to guard a cell against damage or death by acting as chaperones facilitating aberrant protein removal and appropriate polypeptide folding.