WIN55212-2 alleviates acute kidney injury in septic mice by regulating the AKT/mTOR/PFKFB3 signaling pathway

To investigate the effects of cannabinoid receptor agonist, WIN55212-2 (WIN), on acute kidney injury (AKI) in mice with sepsis and its underlying mechanism.

Twenty-four healthy male mice were divided into (n=6): Control group, sepsis group (LPS group), sepsis+WIN55212-2 group (LPS+WIN group) and sepsis+WIN55212-2+mTOR activator MHY1485 group (LPS+WIN+MHY group). The sepsis model was constructed by intraperitoneal injection of LPS. After the tissue and blood samples were harvested in 24 h after modeling, ELISA was used to determine the contents of IL-1β, IL-18 and lactate dehydrogenase A (LDHA) in the renal tissues, as well as Scr, kidney injury molecule-1 (KIM-1) and lactic acid (LA) in the serum. HE staining was employed to observe the pathological changes of kidney tissue and Paller score was calculated. The expression of p-AKT, p-mTOR and 6-phosphofructokinase-2/fructose-2, 6-biphosphatase 3 (PFKFB3) in the renal tissues was detected by Western blotting.

Compared with the Control group, the LPS group had obvious kidney tissue damage, increased Paller score (P < 0.05), increased serum contents of lactic acid, Scr and KIM-1 (P < 0.05), up-regulated contents of LDHA, IL-1β and IL-18 in the renal tissues (P < 0.05), and elevated expression levels of p-AKT, p-mTOR and PFKFB3 in the renal tissues (P < 0.05). Milder pathological injury in kidney tissue, decreased Paller score (P < 0.05), reduced contents of lactic acid, Scr and KIM-1 (P < 0.05), decreased contents of LDHA, IL-1β and IL-18 (P < 0.05), and lower expression of p-AKT, p-mTOR and PFKFB3 were observed in the LPS+WIN group than the LPS group (P < 0.05). The LPS+WIN+MHY group had notably higher Paller score (P < 0.05), raised contents of lactic acid, Scr and KIM-1 (P < 0.05), increased contents of LDHA, IL-1β and IL-18 (P < 0.05), and up-regulated expression of p-AKT, p-mTOR and PFKFB3 (P < 0.05) when compared with the LPS+WIN group.

WIN can alleviate AKI in sepsis, and it may reduce the level of glycolysis in renal tissue, and alleviate inflammation through inhibiting AKT/mTOR/PFKFB3 signaling pathway.