LAUSR

Objectives: The sphingosine-1-phosphate (S1P) receptor modulator FTY720 exerts pleiotropic effects on the cardiovascular system. We examined the effects of long term FTY720 treatment on mineralocorticoid/salt-induced renal injury. Methods: Uninephrectomized rats on 0.9% NaCl/0.3% KCl drinking solution were randomly divided into control, control+FTY720, DOCA, and DOCA+FTY720 groups and administered vehicle, vehicle+FTY720, DOCA+vehicle, and DOCA+FTY720 for 4 weeks, respectively. Results: Only the DOCA+FTY720 group had reduced survival rates. Both the DOCA+FTY720 and DOCA groups developed malignant hypertension, which was more severe in the DOCA+FTY720 group. In the DOCA+FTY720 group only, thrombotic microangiopathy (TMA) involving severe renal arteriole endothelial cell injury was observed with hemolysis due to intravascular mechanical fragmentation of erythrocytes and thrombocytopenia. Expression levels of vascular endothelial growth factor, S1P receptor 1, and S1P receptor 3 in renal arteriole endothelial cells were significantly greater in the DOCA+FTY720 and DOCA groups compared with the control group, with levels being similar between the two groups. Expression levels of endothelial nitric oxide synthase in renal arteriole endothelial cells were significantly lower in the DOCA+FTY720 group only. There were fewer circulating endothelial progenitor cells in the DOCA+FTY720 group but more in the DOCA group compared with the control group. The control+FTY720 group showed reduced circulating endothelial progenitor cells, but no significant functional or pathological changes in kidneys or changes in blood pressure. Conclusion: Exposure of uninephrectomized rats to DOCA/salt+FTY720 for 4 weeks induced renal arteriolar endothelial cell injury, resulting in the development of TMA.