OMEPRAZOLE INHIBITS INFLAMMATORY RESPONSE BY BLOCKING THE TLR4/NF-ΚB SIGNALLING PATHWAY AND PLAYS A PROTECTIVE ROLE AGAINST CISPLATIN-INDUCED KIDNEY INJURY

Qi Yu¹, Yongmei Guo², Xiaoting Xu³, Xuejiao Ding⁴, Huayan Zhang⁵, Guanjun Luo⁶, Chuanlin Zhang^5*

¹Department of Nephrology, The First Affiliated Hospital of Jiangxi Medical College, Shangrao 334000, Jiangxi Province, China - ²Department of Pharmacology, Jiangxi Medical College, Shangrao 334000, Jiangxi Province, China - ³Department of Pharmacy, The Shangrao People's Hospital, Shangrao 334000, Jiangxi Province, China - ⁴Department of Public Health, The First Affiliated Hospital of Jiangxi Medical College, Shangrao 334000, Jiangxi Province, China - ⁵Department of Pharmacy, The First Affiliated Hospital of Jiangxi Medical College, Shangrao 334000, Jiangxi Province, China - ⁶Department of Oncology, The First Affiliated Hospital of Jiangxi Medical College, Shangrao 334000, Jiangxi Province, China

Objective: To investigate the protective effect of omeprazole (OME) on kidney injury induced by cisplatin (CDDP) by inhibiting inflammatory response via blocking the toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) signalling pathway. 

Methods: Twenty-four SPF healthy male SD rats were randomly divided into four groups: a blank control group (control group), cisplatin administration group (CDDP group), cisplatin + omeprazole low-dose group (OME (A)) and cisplatin + omeprazole high-dose group (OME (B)). The control group was injected with an equal volume of normal saline for 5 consecutive days. The CDDP group was injected with an equal volume of normal saline for the first 4 days and then with CDDP (15mg/KGD) on the fifth day. The OME (A) group was injected with an equal volume of OME (1.8mg/KGD) on the first 5 days and then with CDDP (15mg/KGD) 2 hours after the injection on the fifth day. The rats in the OME (B) group were injected with an equal volume of OME (3.6mg/KGD) on the first 5 days and then with CDDP (15mg/KGD) 2 hours after the end of the 5th day. After the end of the OME intervention, the rats were sacrificed. The level of CRE was detected via sarcosine oxidase. BUN level was detected using the urease method. The expression levels of TNF-α, IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of TRaf-6, MyD88, TLR4 and NF-B protein in the cytoplasm of rat kidney tissue. The pathological changes and renal injury of rats were observed, and the western blot results were analysed. 

Results: HE staining showed that when compared to the control group, the renal tissue and tubule epithelium in the CDDP group were severely damaged, the tubules were dilated and swollen, and inflammatory infiltration was obvious. The renal inflammatory response in the OME (A) group was relatively relieved. Moreover, the renal inflammatory response in the OME (B) group was significantly reduced. Compared to the control group, the expression levels of inflammatory factors in the kidney tissues of the CDDP group, OME (A) group and OME (B) group were significantly increased (P<0.05), while those of the OME (A) and OME (B) groups were significantly better than those the CDDP group (P<0.05). Compared to the control group, renal function in the CDDP group, OME (A) group and OME (B) group was significantly decreased (P<0.05), while that of the OME (A) and OME (B) groups was significantly better than that of the CDDP group (P<0.05). There was no significant difference in kidney weight among all groups (P>0.05). Compared to the control group, the kidney index values of the CDDP group, OME (A) group and OME (B) group were significantly higher (P<0.05), while those of the OME (A) and OME (B) groups were significantly better than those of the CDDP group (P<0.05). Compared to the control group, the levels of GSH and SOD in the CDDP group, OME (A) group and OME (B) group were significantly decreased (P<0.05), while the levels of MDA in the CDDP group and OME (A) group were significantly lower than those in OME (B) group (P<0.05). The CDDP group and OME (A) group were significantly higher than OME (B) group (P<0.05). Compared to the control group, the expression levels of TRAF-6, MyD88, TLR4 and nuclear NF-B protein in the kidney tissues of the CDDP group, OME (A) group and OME (B) group were significantly higher than those in the CDDP group (P<0.05). 

Conclusion: OME can reduce the inflammatory response induced by CDDP in the kidney of rats, reduce the expression level of inflammatory factors, prevent the activation of the TLR4/NF-B signalling pathway and effectively alleviate the damage caused by CDDP to kidney tissue.