Original Paper

Apoptosis

, Volume 17, Issue 12, pp 1261-1274

First online:

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

  • María del NogalAffiliated withDepartment of Physiology, Facultad de Medicina, Universidad de AlcaláIRSINREDinREN (Instituto de Salud Carlos III)
  • , Alicia LuengoAffiliated withDepartment of Physiology, Facultad de Medicina, Universidad de AlcaláIRSINREDinREN (Instituto de Salud Carlos III)
  • , Gemma OlmosAffiliated withDepartment of Physiology, Facultad de Medicina, Universidad de AlcaláIRSINREDinREN (Instituto de Salud Carlos III)
  • , Marina LasaAffiliated withDepartamento de Bioquímica–Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid
  • , Diego Rodriguez–PuyolAffiliated withDepartment of Medicine, Universidad de AlcaláNephrology Section and Research Unit Foundation, Hospital Universitario Príncipe de AsturiasIRSINREDinREN (Instituto de Salud Carlos III)
  • , Manuel Rodriguez–PuyolAffiliated withDepartment of Physiology, Facultad de Medicina, Universidad de AlcaláIRSINREDinREN (Instituto de Salud Carlos III)
  • , Laura CallerosAffiliated withDepartment of Physiology, Facultad de Medicina, Universidad de AlcaláIRSINREDinREN (Instituto de Salud Carlos III) Email author 

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Abstract

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.

Keywords

Apoptosis NFκB ILK Cell–matrix-interactions Collagen Renal fibrosis