The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB
Author
Moreno, Juan A.; Izquierdo, María Concepción; Sánchez Niño, María Dolores


Entity
UAM. Departamento de MedicinaPublisher
American Society of NephrologyDate
2011-07-01Citation
10.1681/ASN.2010101073
Journal of the American Society of Nephrology 22.7 (2011): 1315-1325
ISSN
1046-6673 (print); 1533-3450 (online)DOI
10.1681/ASN.2010101073Funded by
Grant support: ISCII and FEDER funds CP04/ 00060, PS09/00447, 06/0046, SAF2005–03378, EU QLG1-CT-2002-01215, Sociedad Española de Nefrologia, ISCIIIRETIC REDinREN/RD06/0016, Comunidad de Madrid/CIFRA/SBIO0283/ 2006, Ministerio de Ciencia y Tecnología (SAF2007/63648, PI10/00072), CAM (S2006/ GEN-0247), RECAVA (RD06/0014/0035;) cvREMOD (091100), IRSIN/FRIAT, FIS PI08/0566. Salary support: FIS to J.A.M. (CD05/00083 and CP10/00479), A.S., and M.C.I., MEC to M.D.S.N., Programa Intensificacion Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to A.OProject
Comunidad de Madrid. S2006/GEN-0247/PROTEOMARKERSEditor's Version
http://dx.doi.org/10.1681/ASN.2010101073Subjects
Cytokines; Inflamotory; Cells; MedicinaRights
© 2011 by the American Society of NephrologyAbstract
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 TWEAKinduced
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.
Files in this item
Google Scholar:Moreno, Juan A.
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Izquierdo, María Concepción
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Sánchez Niño, María Dolores
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Suárez-Álvarez, Beatriz
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López-Larrea, Carlos
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Jakubowski, Aniela
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Blanco-Parra, Jualia A.
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Ramírez Tapia, Rafael
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Selgas Gutiérrez, Rafael
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Ruiz Ortega, Marta
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Egido de los Ríos, Jesús
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Ortiz Arduán, Alberto
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Sanz, Ana Belén
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