phosphate protects against liver IR induced hepatic and renal dysfunction

Since ERK MAPK and Akt signaling pathways are proven to protect against endothelial cell apoptosis and since hepatic IR induced AKI right triggers renal endothelial cell apoptosis with subsequent vascular dysfunction and neutrophil infiltration, we hypothesized that sphinganine 1 phosphate via S1P1 receptormediated activation of ERK MAPK and Akt signaling pathways mapk inhibitor protect against renal endothelial cell apoptosis and reduce AKI after liver IR. Moreover, we've shown previously that improved phosphorylation along with increased synthesis of heat shock protein 27 secured against endothelial cell apoptosis and vascular compromise after hepatic IR. Consequently, we postulated that sphinganine 1 phosphate could also raise HSP27 phosphorylation and upregulation. Finally, since endothelial nitric-oxide synthase up-regulation with therefore increased release of NO shields against vascular endothelial cell injury, and since S1P receptor activation is famous to trigger eNOS Papillary thyroid cancer to improve NO amounts in the vasculature, we postulated that sphinganine 1 phosphate activation of S1P1 receptors may defend against liver and kidney injury via stimulating the eNOS process. In this study, we examined the hypothesis that sphinganine 1 phosphate protects against liver IR induced hepatic and renal dysfunction via S1P1 receptor activation coupled to pertussis toxin sensitive G proteins with subsequent activation of cytoprotective kinases including ERK MAPK and Akt and induction of HSP27 and eNOS in the kidney and liver. We also determined in this research the S1P receptor subtype associated with S1P mediated hepatic and renal protection utilizing both pharmacologic as well as gene knock-down strategies. Reagents Sphinganine 1 phosphate and 3 Dovitinib Amino 4 oxobutylphosphonic acid were obtained from Avanti Polar Lipids, Inc. 5 3 1,2,4 oxadiazole and 1 pyridin 6 yl] 4 semicarbazide were obtained from Tocris Bioscience. 2 undecyl thiazolidine 4 carboxylic acid was purchased from Cayman Chemical. Wortmannin and T N5 ornithine were purchased from EMD Chemicals, Inc. Unless otherwise specified, all the reagents including PD98059 were obtained from Sigma. Murine model of hepatic IR All protocols were accredited by the Institutional Animal Care and Use Committee of Columbia University. As described previously male C57BL/6 rats were subjected to liver IR damage. This technique of partial hepatic ischemia for 60 min. in a segmental hepatic ischemia but spares the right lobe of the liver and prevents mesenteric venous congestion by allowing portal decompression through the right and caudate lobes of the liver. Deception handled mice were put through laparotomy and equivalent liver manipulations without the vascular occlusion. Lcd along with liver and kidney tissues were collected 24 hrs after liver IR injury.