title: Calcineurin inhibitors recruit protein kinases JAK2 and JNK, TLR signaling and the UPR to activate NF-κB-mediated inflammatory responses in kidney tubular cells.
abstract: The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are key drugs in current immunosuppressive regimes for solid organ transplantation. However, they are nephrotoxic and promote death and profibrotic responses in tubular cells. Moreover, renal inflammation is observed in CNI nephrotoxicity but the mechanisms are poorly understood. We have now studied molecular pathways leading to inflammation elicited by the CNIs in cultured and kidney tubular cells. Both CsA and tacrolimus elicited a proinflammatory response in tubular cells as evidenced by a transcriptomics approach. Transcriptomics also suggested several potential pathways leading to expression of proinflammatory genes. Validation and functional studies disclosed that in tubular cells, CNIs activated protein kinases such as the JAK2/STAT3 and TAK1/JNK/AP-1 pathways, TLR4/Myd88/IRAK signaling and the Unfolded Protein Response (UPR) to promote NF-κB activation and proinflammatory gene expression. CNIs also activated an Nrf2/HO-1-dependent compensatory response and the Nrf2 activator sulforaphane inhibited JAK2 and JNK activation and inflammation. A murine model of CsA nephrotoxicity corroborated activation of the proinflammatory pathways identified in cell cultures. Human CNIs nephrotoxicity was also associated with NF-κB, STAT3 and IRE1α activation. In conclusion, CNIs recruit several intracellular pathways leading to previously non-described proinflammatory actions in renal tubular cells. Identification of these pathways provides novel clues for therapeutic intervention to limit CNIs nephrotoxicity.
authors: Renal and Vascular Pathology Laboratory, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Av. Reyes Católicos 2, 28040 Madrid, Spain. Electronic address: cristian.gonzalez@fjd.es.
authors: Cristian
authors: C
authors: González-Guerrero
authors: Carlos
authors: C
authors: Ocaña-Salceda
authors: Sergio
authors: S
authors: Berzal
authors: Susana
authors: S
authors: Carrasco
authors: Beatriz
authors: B
authors: Fernández-Fernández
authors: Pablo
authors: P
authors: Cannata-Ortiz
authors: Jesús
authors: J
authors: Egido
authors: Alberto
authors: A
authors: Ortiz
authors: Adrián M
authors: AM
authors: Ramos
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D053614:Janus Kinase 2 / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009393:Nephritis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D065095:Calcineurin Inhibitors; D018836:Inflammation Mediators; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016572:Cyclosporine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D048670:MAP Kinase Kinase 4; D019703:Calcineurin; D016559:Tacrolimus
keywords: Calcineurin inhibitors; Cyclosporine; Inflammation; NF-κB; Nephrotoxicity; Tacrolimus