Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis

O. Takase, A. W.M. Minto, T. S. Puri, P. N. Cunningham, A. Jacob, M. Hayashi, R. J. Quigg

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Apoptosis and inflammation, important contributors to the progression of chronic kidney disease, can be influenced by clusterin (a secreted glycoprotein that regulates apoptosis) and nuclear factor-κB (NF-κB, a transcription factor modifying the expression of inflammatory genes). We studied proteinuria-induced renal disease and its influence on clusterin-mediated apoptosis. Exposure of cultured mouse proximal tubule epithelial cells to bovine serum albumin (BSA) resulted in activation of NF-κB and activator protein-1 (AP-1) within hours followed by a decline in their activation, decreased activation of extracellular signal-regulated kinases (ERK1/2), decreased cell-associated antiapoptotic Bcl-xL protein but increased apoptosis. Clusterin progressively increased in the media over a 3 day period. Clusterin siRNA blocked protein production, increased NF-κB activation, and significantly increased cellular Bcl-xL protein, thereby reducing spontaneous and BSA-induced apoptosis. An siRNA to the NF-κB inhibitor IκBα had similar results. BSA-stimulated NF-κB activation reciprocally decreased AP-1 activity by preventing ERK1/2 phosphorylation. These in vitro studies suggest that clusterin inhibits NF-κB-mediated antiapoptotic effects by the apparent stabilization of IκBα switching from promoting inflammation to apoptosis during proteinuria.

Original languageEnglish
Pages (from-to)567-577
Number of pages11
JournalKidney international
Volume73
Issue number5
DOIs
Publication statusPublished - 2008 Mar

    Fingerprint

Keywords

  • Apoptosis
  • Complement
  • Epithelial
  • Progression of chronic renal failure
  • Proteinuria
  • Signaling

ASJC Scopus subject areas

  • Nephrology

Cite this

Takase, O., Minto, A. W. M., Puri, T. S., Cunningham, P. N., Jacob, A., Hayashi, M., & Quigg, R. J. (2008). Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis. Kidney international, 73(5), 567-577. https://doi.org/10.1038/sj.ki.5002563