Balance between apoptosis or survival induced by changes in extracellular-matrix composition in human mesangial cells: a key role for ILK-NFκB pathway.
Renal fibrosis is the final outcome of many clinical conditions that lead to chronic renal failure, characterized by a progressive substitution of cellular elements by extracellular-matrix proteins, in particular collagen type I. The aim of this study was to identify the mechanisms responsible for human mesangial cell survival, conditioned by changes in extracellular-matrix composition. Our results indicate that collagen I induces apoptosis in cells but only after inactivation of the pro-survival factor NFκB by either the super-repressor IκBα or the PDTC inhibitor. Collagen I activates a death pathway, through ILK/GSK-3β-dependent Bim expression. Moreover, collagen I significantly increases NFκB-dependent transcription, IκBα degradation and p65/NFκB translocation to the nucleus; it activates β1 integrin and this is accompanied by increased activity of ILK which leads to AKT activation. Knockdown of ILK or AKT with small interfering RNA suppresses the increase in NFκB activity. NFκB mediates cell survival through the antiapoptotic protein Bcl-xL. Our data suggest that human mesangial cells exposed to abnormal collagen I are protected against apoptosis by a complex mechanism involving integrin β1/ILK/AKT-dependent NFκB activation with consequent Bcl-xL overexpression, that opposes a simultaneously activated ILK/GSK-3β-dependent Bim expression and this dual mechanism may play a role in the progression of glomerular dysfunction.
Department of Physiology, Facultad de Medicina, Universidad de Alcalá, Campus Universitario s/n, Alcalá de Henares, 28871 Madrid, Spain.
María
M
del Nogal
Alicia
A
Luengo
Gemma
G
Olmos
Marina
M
Lasa
Diego
D
Rodriguez-Puyol
Manuel
M
Rodriguez-Puyol
Laura
L
Calleros
D017209:Apoptosis; D002470:Cell Survival; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
D024042:Collagen Type I; D019012:Integrin beta1; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK