P0521TICAGRELOR PROTECTS KIDNEY FROM SEPSIS INDUCED ACUTE KIDNEY INJURY THROUGH ADENOSINE DEPENDENT WAY

Abstract

Abstract Background and Aims Sepsis induced acute kidney injury (AKI) is common in intensive care unit in multiple organ failure patients. Ticagrelor is an anti-platelet drug that widely applied in coronary artery disease. In addition, ticagrelor can increase the level of adenosine. Recent study had indicated that ticagrelor can protect renal function in sepsis induced AKI. However, the detailed mechanism was still unknown. Accordingly, we designed this trial to investigate if the ticagrelor alleviated sepsis induced AKI and demonstrated the potential mechanism that how ticagrelor works. Method C57BL6J mouse received oral ticagrelor (20mg/kg and 50mg/kg) for 7 days and caecum ligation and puncture (CLP) were performed. Adenosine-receptor antagonist was administered (10mg/kg, intraperitoneal injection) to block the adenosine pathway 2h before CLP. After 24h, serum creatinine was measured. PAS staining was used and TUNEL staining was applied to determine the pathological changes and cell apoptosis. Plasma concentrations of TNF-α and IL-1β were detected. Kidney tissue level of TNF-α and IL-1β were determined via qRT-PCR. Western blot was used to determine the expression of signal molecular in kidney. Results In ticagrelor group, PAS staining (fig. 1) showed that less swelling of renal tubules and TUNEL staining (fig. 2) showed the less cell apoptosis compared to CLP. Serum creatinine was significantly lower in ticagrelor group. Plasma TNF-α and IL-1β and kidney expression of TNF-α and IL-1β were significantly lower in ticagrelor group. Adenosine-receptor antagonist significantly blocked the effect of ticagrelor (fig. 3 ang 4). Western blot showed that ticagrelor activate the phosphorylation of AKT and mTOR in kidney. Adenosine-receptor antagonist inhibited the activation of AKT and mTOR (fig. 5). Conclusion The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of phosphorylation of AKT and mTOR in sepsis induced AKI.