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

Kidney Int. 2008 Mar;73(5):567-77. doi: 10.1038/ Epub 2007 Dec 12.


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-kappaB (NF-kappaB, 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-kappaB 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-kappaB activation, and significantly increased cellular Bcl-xL protein, thereby reducing spontaneous and BSA-induced apoptosis. An siRNA to the NF-kappaB inhibitor IkappaBalpha had similar results. BSA-stimulated NF-kappaB activation reciprocally decreased AP-1 activity by preventing ERK1/2 phosphorylation. These in vitro studies suggest that clusterin inhibits NF-kappaB-mediated antiapoptotic effects by the apparent stabilization of IkappaBalpha switching from promoting inflammation to apoptosis during proteinuria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Chronic Disease
  • Clusterin / antagonists & inhibitors
  • Clusterin / genetics
  • Clusterin / metabolism*
  • Cytochromes c / metabolism
  • I-kappa B Kinase / metabolism
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology*
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology*
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • NF-kappa B / metabolism*
  • RNA, Small Interfering / pharmacology
  • Serum Albumin, Bovine / toxicity
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor RelA / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / genetics


  • Clusterin
  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factor AP-1
  • Transcription Factor RelA
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Serum Albumin, Bovine
  • Cytochromes c
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases