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Non-canonical NFκB activation promotes chemokine expression in podocytes

Lara Valiño-Rivas1,2, Laura Gonzalez-Lafuente1,2, Ana B Sanz1,2

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

Scientific Reports
|June 30, 2016
PubMed

Insights

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) activates non-canonical NFκB signaling in kidney podocytes. This pathway upregulates chemokine CCL21, a potential therapeutic target for proteinuric kidney diseases.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Podocyte expression of the TWEAK receptor Fn14 is linked to protection from proteinuric kidney disease.
  • Downstream signaling pathways of TWEAK/Fn14 in podocytes remain largely uncharacterized.
  • Understanding these pathways is crucial for developing targeted therapies for kidney disease.

Purpose of the Study:

  • To investigate the role of TWEAK activation in non-canonical NFκB signaling within cultured podocytes.
  • To identify downstream molecular targets of TWEAK/Fn14 signaling in podocytes.
  • To explore the therapeutic potential of targeting the non-canonical NFκB pathway in proteinuric kidney disease.

Main Methods:

  • Cultured podocytes were treated with TWEAK to analyze chemokine expression (CCL21, CCL19, RANTES).
  • NFκB signaling pathways (canonical and non-canonical) were assessed using specific inhibitors and siRNA targeting NIK (NF-κB-inducing kinase).
  • Expression of Fn14 and CCL21 was evaluated in a rat model of puromycin-induced proteinuric kidney disease.

Main Results:

  • TWEAK stimulation increased CCL21, CCL19, and RANTES expression in podocytes.
  • TWEAK induced non-canonical NFκB activation, evidenced by NFκB2/p100 processing and RelB/p52 nuclear translocation.
  • NIK silencing specifically blocked TWEAK-induced CCL21 upregulation, identifying CCL21 as a non-canonical NFκB target in podocytes.
  • Elevated kidney Fn14 and CCL21 expression, localized to podocytes, was observed in a rat model of proteinuric kidney disease.

Conclusions:

  • TWEAK activates the non-canonical NFκB pathway in podocytes.
  • This activation leads to the upregulation of CCL21, a key chemokine.
  • The non-canonical NFκB pathway represents a promising therapeutic target for managing proteinuric kidney diseases.

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