Apoptosis

, Volume 17, Issue 12, pp 1261–1274

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 Nogal
  • Alicia Luengo
  • Gemma Olmos
  • Marina Lasa
  • Diego Rodriguez–Puyol
  • Manuel Rodriguez–Puyol
  • Laura Calleros
Original Paper

DOI: 10.1007/s10495-012-0769-3

Cite this article as:
del Nogal, M., Luengo, A., Olmos, G. et al. Apoptosis (2012) 17: 1261. doi:10.1007/s10495-012-0769-3

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

ApoptosisNFκBILKCell–matrix-interactionsCollagenRenal fibrosis

Abbreviations

HMC

Human mesangial cells

ECM

Extracellular matrix

COL I

Collagen type I

COL IV

Collagen type IV

NFκB

Nuclear factor κB

IκB

Inhibitor of NFκB

ILK

Integrin-linked kinase

GSK-3β

Glycogen synthase kinase-3 β

Supplementary material

10495_2012_769_MOESM1_ESM.doc (46 kb)
Supplementary material 1 (DOC 45 kb)
10495_2012_769_MOESM2_ESM.doc (575 kb)
Supplementary material 2 (DOC 575 kb)

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • María del Nogal
    • 1
    • 5
    • 6
  • Alicia Luengo
    • 1
    • 5
    • 6
  • Gemma Olmos
    • 1
    • 5
    • 6
  • Marina Lasa
    • 4
  • Diego Rodriguez–Puyol
    • 2
    • 3
    • 5
    • 6
  • Manuel Rodriguez–Puyol
    • 1
    • 5
    • 6
  • Laura Calleros
    • 1
    • 5
    • 6
  1. 1.Department of Physiology, Facultad de MedicinaUniversidad de AlcaláMadridSpain
  2. 2.Department of MedicineUniversidad de AlcaláMadridSpain
  3. 3.Nephrology Section and Research Unit FoundationHospital Universitario Príncipe de AsturiasMadridSpain
  4. 4.Departamento de Bioquímica–Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones CientíficasUniversidad Autónoma de MadridMadridSpain
  5. 5.IRSINMadridSpain
  6. 6.REDinREN (Instituto de Salud Carlos III)MadridSpain