EFFECT OF TLR4/MYD88/NF-ΚB SIGNALLING ON RENAL INJURY CAUSED BY SEPSIS

Objective: The purpose of this study was to explore the effects of TLR4/MyD88/NF-κB on the kidneys during sepsis. Methods: In this experiment, three types of mice—normal mice, TLR4 gene-deficient mice and MyD88 gene-deficient mice—were used to establish a kidney sepsis injury model by cecal ligation puncture (CLP). The animals were divided into four groups: (a) Control group (normal mice without any treatment), (b) WT group (normal mice with CLP treatment), (c) TLR4-/group (mice with TLR4 gene defect and CLP treatment), and (d) MyD88-/group (mice with MyD88 gene defect and CLP treatment). We observed the effect of CLP-induced sepsis on the survival rate and intraabdominal bacteria found in different groups, reporting on the level of serum creatine anhydride and blood urea, renal tubule necrosis and the expression of genes related to renal injury. In addition, we analysed the activity of NF-κB p65 in different groups of mice with CLPinduced sepsis using the immunohistochemical technique. Results: (1) After 192 h of CLP-induced sepsis, the MyD88 gene defect group had the highest survival rate, but also the highest number of bacteria in the abdominal cavity. The total survival time of TLR4-/group was longer than that of the WT group, and the number of bacteria in the abdominal cavity was less than that of the WT group. (2) Concentrations of serum creatinine and blood urea were significantly reduced in the MyD88-/gene defect group as compared with the WT group (P<0.001), while serum creatinine and blood urea concentrations in the TLR4-/group were improved, this improvement was not statistically significant (P>0.05). Compared with the WT mice, the expression of kidney damage molecular-1 (KIM-1) gene in TLR4-/group was significantly decreased (P<0.01), and the expression of KIM-1 was significantly decreased in MyD88-/mice (P<0.001). (3) The kidney tissue of mice in the MyD88-/group was similar to that in the control group, with almost no damage. Compared with WT mice, the expression of TLR4-related ligands HMGB1 and HSP70 in the MyD88-/group was also significantly reduced. (4) Compared with the WT group, mRNA expressions of IL1β, IL-6 and TNF-α in the TLR4-/and MyD88-/groups were lower, with statistical significance (P<0.05). (5) Immunohistochemical results showed that the absence of TLR4 and MyD88 affected the activity of NF-κB p65 in sepsis mice, and the translocation of NF-κB p65 into the nucleus was significantly protected. Conclusion: The deletion of the TLR4/MyD88 gene can reduce the effects of sepsis on renal injury, can reduce the expression of related inflammatory factors and can inhibit the activity of NF-κB p65.Therefore, it is possible that the functional mechanism of sepsis on renal injury is related to the TLR4/Myd88/NF-κB signalling pathway.