Mechanistic Of Action Of HMGB1 In Regulating Acute Kidney Injury Associated With Urogenic Sepsis

Objective:To establish an animal model of ureter-induced sepsis,to simulate acute kidney injury caused by acute ureteral obstructive infection,to explore the mechanism of action of high-mobility group protein B1 in regulating acute kidney injury associated with urogenic sepsis,and to provide a theoretical basis for the potential treatment of acute kidney injury associated with ureter-induced sepsis.Methods:Twenty male healthy New Zealand rabbits were divided into four groups of 5rabbits,namely control group,sham group,sepsis group,sepsis+glycyrrhizic acid group.The control group did not do any treatment and was only given a free diet of feed.In the sham group,the middle and upper part of the left ureter was exposed,and no other treatment was done,and the sepsis group injected Escherichia coli(ATCC 25922)at a concentration of 10~8cfu/m L into the left ureter of the rabbit,and then ligated the distal end of the ureter with silk thread to replicate the model of ureteral acute obstruction and infection with urogenic sepsis.The sepsis+glycyrrhizic acid group was given 5 mg/kg of glycyrrhizic acid solution intravenously through the ear margin on the basis of the sepsis group for 3 days.At 72 h after surgery,peripheral blood white blood cell count,neutrophil count,C-reactive protein,serum creatinine and urea nitrogen were measured in each group.The contents of HMGB1,TNF-α,IL-1βand IL-6 in serum were determined by ELISA method.HE staining of kidney tissues of each group was taken to evaluate inflammatory infiltration and tubular injury.q PCR,Western-blot and IHC were used to detect the expression of related signaling pathway molecules such as HMGB1,TLR4,NF-κB P65 in the kidney.Results:There were no significant differences in serum leukocyte,neutrophil and C-reactive protein expression in the sham group compared with the control group.The serum white blood cell count,neutrophil count and C-reactive protein levels in the sepsis group were significantly higher than those in the sham group(P<0.01).After 72 h of GA treatment,the levels of leukocytes,neutrophils and C-reactive protein in the serum of rabbits in the sepsis group(P<0.05)were significantly reduced.The serum serum creatinine and urea nitrogen levels in rabbits in the sepsis group were significantly higher than those in the sham group(P<0.01).GA treatment could reduce serum creatinine and urea nitrogen levels in rabbits in the sepsis group(P<0.05)after 72 h.The serum levels of HMGB1,TNF-α,IL-1βand IL-6 in rabbits in the sepsis group were significantly higher than those in the sham group(P<0.01).After 72 h of GA treatment,the serum levels of HMGB1,TNF-α,IL-1βand IL-6(P<0.05)in rabbits with sepsis group could be reduced.The levels of TLR4 and NF-κB p65proteins in the kidney tissues of rabbits in the sepsis group were significantly increased.After GA treatment,TLR4/NF-κB signaling pathway activation was significantly inhibited.Conclusion:1.HMGB1 is associated with urogenic sepsis-induced AKI,glycyrrhizic acid can significantly reduce the expression of inflammatory mediators,improve renal function,and reduce AKI by blocking HMGB1 expression;2.Glycyrrhizic acid alleviates urogenic sepsis-related AKI by regulating the HMGB1/TLR4/NF-κB signaling pathway,It was suggested that HMGB1 was an important regulatory target for urogenic sepsis-related AKI.