title: Integrin-linked kinase plays a key role in the regulation of angiotensin II-induced renal inflammation.
abstract: ILK (integrin-linked kinase) is an intracellular serine/threonine kinase involved in cell-matrix interactions. ILK dysregulation has been described in chronic renal disease and modulates podocyte function and fibrosis, whereas data about its role in inflammation are scarce. AngII (angiotensin II) is a pro-inflammatory cytokine that promotes renal inflammation. AngII blockers are renoprotective and down-regulate ILK in experimental kidney disease, but the involvement of ILK in the actions of AngII in the kidney has not been addressed. Therefore we have investigated whether ILK signalling modulates the kidney response to systemic AngII infusion in wild-type and ILK-conditional knockout mice. In wild-type mice, AngII induced an inflammatory response, characterized by infiltration of monocytes/macrophages and lymphocytes, and up-regulation of pro-inflammatory factors (chemokines, adhesion molecules and cytokines). AngII activated several intracellular signalling mechanisms, such as the NF-κB (nuclear factor κB) transcription factor, Akt and production of ROS (reactive oxygen species). All these responses were prevented in AngII-infused ILK-deficient mice. In vitro studies characterized further the mechanisms regulating the inflammatory response modulated by ILK. In cultured tubular epithelial cells ILK blockade, by siRNA, inhibited AngII-induced NF-κB subunit p65 phosphorylation and its nuclear translocation. Moreover, ILK gene silencing prevented NF-κB-related pro-inflammatory gene up-regulation. The results of the present study demonstrate that ILK plays a key role in the regulation of renal inflammation by modulating the canonical NF-κB pathway, and suggest a potential therapeutic target for inflammatory renal diseases.
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Alique
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Civantos
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Sanchez-Lopez
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lavoz
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrigues-Díez
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: García-Redondo
authors.affiliation: †Renal Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, CIBERDEM, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: ‡Dialysis Unit, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: §Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
authors.affiliation: ¶Physiology Department, Universidad de Alcalá, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol
authors.affiliation: *Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D020868:Gene Silencing; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D000099200:Scaffold Protein ILK
chemical_list: D000804:Angiotensin II; D018836:Inflammation Mediators; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000099200:Scaffold Protein ILK