Inhibition of NF-kappaB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis.
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.
Takase
O
O
Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA. otakase-tky@umin.ac.jp
Minto
A W M
AW
Puri
T S
TS
Cunningham
P N
PN
Jacob
A
A
Hayashi
M
M
Quigg
R J
RJ
D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D051152:Clusterin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics
D051152:Clusterin; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D012710:Serum Albumin, Bovine; D045304:Cytochromes c; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases