title: Sorafenib Inhibits Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Inhibition of Macrophage Infiltration.
abstract: OBJECTIVE
  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-β1-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.
authors.affiliation: Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Ma
authors.forename: Le
authors.initials: L
authors.lastname: Tao
authors.forename: Xuefei
authors.initials: X
authors.lastname: Wang
authors.forename: Qinyi
authors.initials: Q
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Li
authors.forename: Chunfeng
authors.initials: C
authors.lastname: He
authors.forename: Dongying
authors.initials: D
authors.lastname: Xue
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D054371:Chemokine CXCL11 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000077157:Sorafenib; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology; D014513:Ureter / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D018932:Chemokine CCL2; D054371:Chemokine CXCL11; D009536:Niacinamide; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D000077157:Sorafenib; D053773:Transforming Growth Factor beta1; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; C508961:Tgfb1 protein, mouse