title: TLR4-mediated inflammation is a key pathogenic event leading to kidney damage and fibrosis in cyclosporine nephrotoxicity.
abstract: Cyclosporine A (CsA) successfully prevents allograft rejection, but nephrotoxicity is still a dose-limiting adverse effect. TLR4 activation promotes kidney damage but whether this innate immunity receptor mediates CsA nephrotoxicity is unknown. The in vivo role of TLR4 during CsA nephrotoxicity was studied in mice co-treated with CsA and the TLR4 inhibitor TAK242 and also in TLR4-/-mice. CsA-induced renal TLR4 expression in wild-type mice. Pharmacological or genetic targeting of TLR4 reduced the activation of proinflammatory signaling, including JNK/c-jun, JAK2/STAT3, IRE1α and NF-κB and the expression of Fn14. Expression of proinflammatory factors and cytokines was also decreased, and kidney monocyte and lymphocyte influx was prevented. TLR4 inhibition also reduced tubular damage and drastically prevented the development of kidney fibrosis. In vivo and in vitro CsA promoted secretion of the TLR ligand HMGB1 by tubular cells upstream of TLR4 activation, and prevention of HMGB1 secretion significantly reduced CsA-induced synthesis of MCP-1, suggesting that HMGB1 may be one of the mediators of CsA-induced TLR4 activation. These results suggest that TLR4 is a potential pharmacological target in CsA nephrotoxicity.
authors: Laboratory of Nephrology and Vascular Pathology, IIS-Fundación Jiménez Díaz, School of Medicine, Madrid, Spain.|REDINREN, Madrid, Spain.
authors: Cristian
authors: C
authors: González-Guerrero
authors: REDINREN, Madrid, Spain.|Pathology, IIS-Fundación Jiménez Díaz, School of Medicine, UAM, Madrid, Spain.
authors: Pablo
authors: P
authors: Cannata-Ortiz
authors: Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Consuelo
authors: C
authors: Guerri
authors: Laboratory of Nephrology and Vascular Pathology, IIS-Fundación Jiménez Díaz, School of Medicine, Madrid, Spain.|Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Madrid, Spain.
authors: Jesús
authors: J
authors: Egido
authors: Laboratory of Nephrology and Vascular Pathology, IIS-Fundación Jiménez Díaz, School of Medicine, Madrid, Spain.|REDINREN, Madrid, Spain.|Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Madrid, Spain.
authors: Alberto
authors: A
authors: Ortiz
authors: Laboratory of Nephrology and Vascular Pathology, IIS-Fundación Jiménez Díaz, School of Medicine, Madrid, Spain. amramos@fjd.es.|REDINREN, Madrid, Spain. amramos@fjd.es.|Laboratorio de Patología Renal y Vascular (Investigación, 4° planta), Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Av. Reyes Católicos N°2, CP28040, Madrid, Spain. amramos@fjd.es.
authors: Adrián M
authors: AM
authors: Ramos
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D024243:HMGB1 Protein / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D007166:Immunosuppressive Agents; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D016572:Cyclosporine
keywords: Cyclosporine A; Fibrosis; Inflammation; Innate immunity; Nephrotoxicity; TLR4