Extracellular matrix regulates glomerular epithelial cell survival and proliferation

Am J Physiol Renal Physiol. 2004 Feb;286(2):F255-66. doi: 10.1152/ajprenal.00259.2003. Epub 2003 Oct 14.

Abstract

Glomerular epithelial cell (GEC) injury and apoptosis may contribute to sclerosis in glomerulonephritis. The present study addresses signals that regulate survival of GEC in culture and in the acute puromycin aminonucleoside nephrosis (PAN) model of GEC injury in vivo. Compared with GEC on plastic substratum, adhesion to collagen increased activation of focal adhesion kinase (FAK), c-Src, and ERK and facilitated survival (prevented apoptosis). GEC on plastic exhibited increased caspase-8 and -9 activities, increased expression of the proapoptotic protein, Bax, and decreased the antiapoptotic protein, Bcl-XL, compared with collagen. Stable expression of constitutively active mutants of FAK (CD2-FAK) or MEK (R4F-MEK) activated the ERK pathway and supplanted the requirement of collagen for survival. In contrast, expression of a Ras mutant that activates phosphatidylinositol 3-kinase but blocks ERK activation or pharmacological inhibition of the ERK pathway decreased survival on collagen. Glomeruli isolated from rats with PAN revealed increased beta1-integrin expression, along with increased activation of FAK, c-Src, and ERK, compared with controls. EGF receptor activation was undetectable in PAN. Therefore, adhesion to collagen, resulting in activation of FAK and the Ras-ERK pathway, supports GEC survival. Analogous signals for GEC survival are activated in PAN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CSK Tyrosine-Protein Kinase
  • Caspases / metabolism
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Division / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Collagen / pharmacology
  • Enzyme Activation / drug effects
  • Extracellular Matrix / metabolism*
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Gene Expression Regulation, Enzymologic
  • Growth Substances / pharmacology
  • Kidney Glomerulus / cytology*
  • Kidney Glomerulus / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / physiology
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Nephrosis / chemically induced
  • Nephrosis / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Puromycin Aminonucleoside
  • Rats
  • Rats, Sprague-Dawley
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • ras Proteins / metabolism
  • src-Family Kinases

Substances

  • Bax protein, rat
  • Bcl2l1 protein, rat
  • Growth Substances
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Puromycin Aminonucleoside
  • Collagen
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Ptk2 protein, rat
  • src-Family Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Caspases
  • ras Proteins