Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis

Duane Delimont, Brianna M. Dufek, Daniel T. Meehan, Marisa L Zallocchi, Michael Anne Gratton, Grady Phillips, Dominic E Cosgrove

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

It has been known for some time that laminins containing α1 and α2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM) of Alport mice, dogs, and humans. We show that laminins containing the α2 chain, but not those containing the α1 chain activates focal adhesion kinase (FAK) on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of α2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP- 12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin α2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages.

Original languageEnglish (US)
Article numbere99083
JournalPloS one
Volume9
Issue number6
DOIs
StatePublished - Jun 10 2014

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Focal Adhesion Kinase 2
non-specific protein-tyrosine kinase
Focal Adhesion Protein-Tyrosine Kinases
laminin
Laminin
Matrix Metalloproteinases
basement membrane
stromelysin 2
pathogenesis
Chemical activation
Podocytes
Glomerular Basement Membrane
gelatinase B
mice
interleukin-6
disease models
rendering
urea nitrogen
kidney diseases
Interleukin-6

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. / Delimont, Duane; Dufek, Brianna M.; Meehan, Daniel T.; Zallocchi, Marisa L; Gratton, Michael Anne; Phillips, Grady; Cosgrove, Dominic E.

In: PloS one, Vol. 9, No. 6, e99083, 10.06.2014.

Research output: Contribution to journalArticle

Delimont, Duane ; Dufek, Brianna M. ; Meehan, Daniel T. ; Zallocchi, Marisa L ; Gratton, Michael Anne ; Phillips, Grady ; Cosgrove, Dominic E. / Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. In: PloS one. 2014 ; Vol. 9, No. 6.
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