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The inflammatory cytokines TWEAK and TNF? reduce renal klotho expression through NF?B.


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, TNF?, and siRNA-mediated knockdown of I?B? all activated NF?B and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NF?B with parthenolide prevented TWEAK- or TNF?-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 TNF?, downregulate Klotho expression through an NF?B-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD.

SUBMITTER: Moreno JA 

PROVIDER: S-EPMC3137579 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB.

Moreno Juan A JA   Izquierdo Maria C MC   Sanchez-Niño Maria D MD   Suárez-Alvarez Beatriz B   Lopez-Larrea Carlos C   Jakubowski Aniela A   Blanco Julia J   Ramirez Rafael R   Selgas Rafael R   Ruiz-Ortega Marta M   Egido Jesus J   Ortiz Alberto A   Sanz Ana B AB  

Journal of the American Society of Nephrology : JASN 20110630 7


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 TWEA  ...[more]

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