title: The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB.
abstract: Proinflammatory cytokines contribute to renal injury, but the downstream effectors within kidney cells are not well understood. One candidate effector is Klotho, a protein expressed by renal cells that has antiaging properties; Klotho-deficient mice have an accelerated aging-like phenotype, including vascular injury and renal injury. Whether proinflammatory cytokines, such as TNF and TNF-like weak inducer of apoptosis (TWEAK), modulate Klotho is unknown. In mice, exogenous administration of TWEAK decreased expression of Klotho in the kidney. In the setting of acute kidney injury induced by folic acid, the blockade or absence of TWEAK abrogated the injury-related decrease in renal and plasma Klotho levels. TWEAK, TNFα, and siRNA-mediated knockdown of IκBα all activated NFκB and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NFκB with parthenolide prevented TWEAK- or TNFα-induced downregulation of Klotho. Inhibition of histone deacetylase reversed TWEAK-induced downregulation of Klotho, and chromatin immunoprecipitation showed that TWEAK promotes RelA binding to the Klotho promoter, inducing its deacetylation. In conclusion, inflammatory cytokines, such as TWEAK and TNFα, downregulate Klotho expression through an NFκB-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD.
authors: IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.
authors: Juan A
authors: JA
authors: Moreno
authors: Maria C
authors: MC
authors: Izquierdo
authors: Maria D
authors: MD
authors: Sanchez-Niño
authors: Beatriz
authors: B
authors: Suárez-Alvarez
authors: Carlos
authors: C
authors: Lopez-Larrea
authors: Aniela
authors: A
authors: Jakubowski
authors: Julia
authors: J
authors: Blanco
authors: Rafael
authors: R
authors: Ramirez
authors: Rafael
authors: R
authors: Selgas
authors: Marta
authors: M
authors: Ruiz-Ortega
authors: Jesus
authors: J
authors: Egido
authors: Alberto
authors: A
authors: Ortiz
authors: Ana B
authors: AB
authors: Sanz
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D015536:Down-Regulation; D005966:Glucuronidase / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D016328:NF-kappa B; D012333:RNA, Messenger; C491645:Tnfsf12 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D006655:Histone Deacetylases