Balance between apoptosis or survival induced by changes in extracellular-matrix composition in human mesangial cells: a key role for ILK-NF kappa B pathway

作者：del Nogal Maria; Luengo Alicia; Olmos Gemma; Lasa Marina; Rodriguez Puyol Diego; Rodriguez Puyol Manuel; Calleros Laura^*

来源：Apoptosis, 2012, 17(12): 1261-1274.

DOI：10.1007/s10495-012-0769-3

• Apoptosis
• NF kappa B
• ILK
• Cell-matrix-interactions
• Collagen
• Renal fibrosis

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 NF kappa B by either the super-repressor I kappa B alpha or the PDTC inhibitor. Collagen I activates a death pathway, through ILK/GSK-3 beta-dependent Bim expression. Moreover, collagen I significantly increases NF kappa B-dependent transcription, I kappa B alpha degradation and p65/NF kappa B translocation to the nucleus; it activates beta 1 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 NF kappa B activity. NF kappa B 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 beta 1/ILK/AKT-dependent NF kappa B activation with consequent Bcl-xL overexpression, that opposes a simultaneously activated ILK/GSK-3 beta-dependent Bim expression and this dual mechanism may play a role in the progression of glomerular dysfunction.

• 出版日期2012-12