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

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-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.

• Authors: O Takase, A W M Minto, T S Puri, P N Cunningham, A Jacob, M Hayashi, R J Quigg
• Journal: Kidney international (Kidney Int) Vol. 73 Issue 5 Pg. 567-77 (Mar 2008) ISSN: 1523-1755 [Electronic] United States
• PMID: 18075502 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

• Animals
• Apoptosis
• Chronic Disease
• Clusterin (antagonists & inhibitors, genetics, metabolism)
• Cytochromes c (metabolism)
• I-kappa B Kinase (metabolism)
• Kidney Diseases (metabolism, pathology)
• Kidney Tubules (drug effects, metabolism, 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, genetics)