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

Juan A Moreno1, Maria C Izquierdo, Maria D Sanchez-Niño

  • 1IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.

Journal of the American Society of Nephrology : JASN
|July 2, 2011
PubMed

Insights

Proinflammatory cytokines like TNF and TWEAK reduce Klotho expression in kidneys via NFκB signaling. This finding links inflammation to aging diseases such as chronic kidney disease (CKD).

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Proinflammatory cytokines are implicated in kidney injury.
  • Klotho, an antiaging protein in renal cells, is a potential mediator.
  • The effect of cytokines like TNF and TWEAK on Klotho is not understood.

Purpose of the Study:

  • To investigate whether tumor necrosis factor (TNF) and TNF-like weak inducer of apoptosis (TWEAK) modulate Klotho expression in kidney cells.
  • To elucidate the molecular mechanisms underlying cytokine-induced Klotho downregulation.

Main Methods:

  • Administration of TWEAK to mice and measurement of renal Klotho levels.
  • Induction of acute kidney injury (AKI) with folic acid and assessment of TWEAK's role.
  • In vitro studies using MCT tubular cells treated with TWEAK, TNFα, or NFκB inhibitors.
  • Chromatin immunoprecipitation (ChIP) to assess transcription factor binding and histone modification.

Main Results:

  • Exogenous TWEAK decreased kidney Klotho expression in mice.
  • TWEAK blockade or absence prevented AKI-induced Klotho reduction.
  • TWEAK, TNFα, and IκBα knockdown activated NFκB and reduced Klotho expression in tubular cells.
  • NFκB inhibition prevented cytokine-induced Klotho downregulation.
  • Histone deacetylase inhibition reversed TWEAK-induced Klotho downregulation, with TWEAK promoting RelA binding and deacetylation at the Klotho promoter.

Conclusions:

  • Inflammatory cytokines, specifically TWEAK and TNFα, downregulate Klotho expression.
  • This downregulation occurs through an NFκB-dependent pathway involving histone modification.
  • These findings may explain the link between inflammation and accelerated organ aging in conditions like chronic kidney disease (CKD).

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