Sphingosine‐1‐phosphate receptor 1 agonist SEW2871 decreases sepsis‐induced renal microvascular permeability but not peritubular capillary hypoperfusion

Abstract

Renal microcirculatory failure and vascular leakage are hallmarks of sepsis‐induced acute kidney injury (AKI). To investigate the mechanism of renal capillary hypoperfusion, the cecal ligation and puncture (CLP) model of sepsis was used in male 40 wk C57BL/6 mice. Since activation of sphingosine‐1‐phosphate receptor 1 (S1P1) has been reported to enhance endothelial barrier function and decrease vascular permeability, mice were administered the S1P1 agonist SEW2871 (1, 3, 10 or 30mg/kg ip) at the time of CLP. Evans blue dye leakage assay was used to measure renal microvascular permeability and intravital video microscopy was used to quantitate changes in renal peritubular capillary perfusion. CLP caused a rapid increase in capillary permeability at 2h, prior to decreased renal capillary perfusion at 4h. SEW2871 dose‐dependently decreased renal vascular permeability at 6h post CLP. However, peritubular capillary perfusion was not improved compared to CLP mice at 6h. Results suggest that renal microvascular leakage is an early event during the development of sepsis and that activation of S1P1 may decrease vascular permeability but cannot prevent the deterioration of renal capillary perfusion. Overall, our study suggested that the early renal capillary hypoperfusion is independent of the increased vascular permeability in CLP septic mice. Supported by AHA 10PRE4140065 (ZW) and NIH DK075991 (PRM).