Aims: Sorafenib, which has been used extensively for the treatment of renal cell cancer and advanced hepatocellular carcinoma (HCC), has also been shown to have antifibrotic effects in liver fibrosis. However, the effects of sorafenib on renal fibrosis are unknown. Therefore, we investigated whether sorafenib inhibited renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and further explored the potential mechanism. Methods: Mice underwent UUO followed by vehicle or sorafenib treatment. The expression of CD68, a macrophage marker, and the pro-inflammatory cytokines, MCP1 and CXCR3, were immunohistochemically analyzed. The involvement of macrophages in the formation of renal fibrosis was studied using confocal microscopy. Results: Renal histopathology improved in the UUO-sorafenib mice. Sorafenib notably suppressed TGF-beta 1-mediated renal fibrogenic effects. The mRNA and protein expressions of CD68, MCP1, and CXCR3 in the obstructed kidney were significantly decreased by sorafenib. Immunohistochemistry showed that CD68 and CXCR3 had a similar distribution, whereas MCP1 was observed predominantly in the tubular epithelial cells. Double immunofluorescence demonstrated that CD68-positive macrophages could co-localize with CXCR3. It also revealed that CXCR3 interacted with CXCL11 in the UUO mouse kidneys. Widespread adhesion of macrophages to myofibroblasts was markedly inhibited in UUO-sorafenib mouse kidneys. Conclusions: Taken together, the results indicated that sorafenib had protective effects against renal fibrosis; its mechanism of action was associated with inhibition of macrophage infiltration via the CXCR3/CXCL11 pathway. These data suggest the clinical potential of sorafenib for treatment of renal fibrosis and illustrate the immunological mechanisms underlying the protective effects of sorafenib. (C) 2016 The Author(s) Published by S. Karger AG, Basel
[1]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Infect Dis, Shanghai, Peoples R China.
[2]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Digest Dis, Shanghai, Peoples R China.
[3]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Cent Lab, Lab Mol Pathol, 164 Lanxi Rd, Shanghai 200062, Peoples R China.
[4]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Gen Surg, Shanghai, Peoples R China.
[5]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Urol, Shanghai, Peoples R China.
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