Chemokine Receptor CX3CR1 Regulates The Development Of Renal Interstitial Fibrosis Through Arginase-1 Signaling Pathway

Renal interstitial fibrosis is a common pathway and pathophysiological basis for the progression of chronic kidney disease caused by various etiologies.CX3CR1 is a chemokine receptor,which mainly combines with CX3CL1 to prompt the migration of inflammatory cells such as monocytes and macrophages to inflammatory sites.Meanwhile,the migration and invasion of macrophages is an important cause of renal fibrosis.There were studies have been reported that interfering with the expression of CX3CR1 in macrophages influence the expression of downstream molecule Arg-1.However,Arg1 pathway plays an important role in the activation and proliferation of M2 macrophages.The purpose of this study was to investigate the mechanism of CX3CR1regulating the function of macrophages through Arg-1 pathway in renal interstitial fibrosis.Methods:Unilateral ureteral obstruction(UUO)was performed in C57BL/B6 mice.Mice were randomly divided into experimental group(CX3CR1inhibitor,2ug/everyday)andcontrol group(Normal saline).The mice were sacrificed in the seventh day and the ligated kidney was removed.Hematoxylin-eosin and Masson staining were used to observe the infiltration of lymphocyte and the progression of fibrosis in the kidney.Reverse transcription-polymerase chain reaction(RT-PCR)and Western blot(WB)were used to detect the expression of CX3CR1,α-SMA,Fibronectin,and Arg-1 in mice kidney.Whole genome sequencing was used to identify differential genes between experimental group and control group.Flow cytometry and RT-PCR were used to verify the results of whole genome sequencing.Results:We found that the expression of CX3CR1 was inhibited by CX3CR1 inhibitor in mice kidney,effectively.The expression ofα-SMA and Fibronectin was significantly lower in experimental group than control group.Simultaneously,the progression of renal interstitial fibrosis and the aggregation of inflammatory cells in the kidney of mice in the experimental group was less than that of control group.The expression of Arg-1 in the renal of mice in the experimental group was significantly higher,accompanied by increased proportion of Arg-1~+CD206~+M2 macrophages.Conclusion:Inhibiting the expression of CX3CR1 in mice can effectively reduce the progression of renal interstitial fibrosis.The mechanism of action is to up regulate the expression of Arg-1 in mice,thereby inducing the differentiation of M2 macrophages.