Abstract 452: Impact of Aryl Hydrocarbon Receptor Agonist, Leflunomide, on Components of Stem Cells in the Setting of Renal Ischemia-Reperfusion Injury

Abstract

The aryl hydrocarbon receptor (AHR) has emerged as a regulator of bone marrow-derived stem cells (BMDSCs). Further, mobilization and homing of BMDSCs into the ischemic-reperfused kidney contribute importantly to the repair and recovery of the injured tissue. We tested the hypothesis that the recently described non-dioxin AHR agonist, leflunomide, mobilizes BMDSCs into the ischemic-reperfused kidney in association with reduction in cell death. Accordingly, male mice were treated with leflunomide (40 mg/kg; i.p.). Thereafter, the right kidney of each animal was subjected to ischemia (45 min) followed by reperfusion (4 hr) while the left kidney served as sham control; vehicle-treated animals served as controls. Peripheral blood and renal cells prepared from kidneys of experimental groups were subjected to flow cytometry-based assays using markers for endothelial progenitor cells (EPCs; Sca1 + /CD31 + ), mesenchymal stem cells (MSCs; Sca1 + /CD11b - ) and hematopoietic stem cells (HSCs; Sca1 + /CD11b + ). Compared to the vehicle-treated mice, peripheral blood of leflunomide-treated mice showed significantly higher levels of MSCs and HSCs with the effect more marked for the latter. On the other hand, the ischemic-reperfused, but not sham, kidneys of leflunomide-treated animals displayed significant and similar increase in the level of each component of BMDSCs compared to their vehicle-treated counterparts. Further, leflunomide-treated mice displayed preservation of mitochondrial membrane potential as well as decreased apoptosis and necrosis compared to vehicle-treated ischemic-reperfused or sham kidneys. Collectively, the results indicate that AHR stimulation may represent a novel renoprotective mechanism likely involving mobilization and recruitment of components of Sca1+ stem cells into the damaged kidney.