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1 Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: andrey.cybulsky{at}mcgill.ca.
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 extracellular signal-regulated kinase (ERK), and facilitated
survival (prevented apoptosis). GEC on plastic exhibited increased caspase 8 and 9 activities, increased expression of the pro-apoptotic protein, Bax, and decreased anti-apoptotic protein, Bcl-XL, as compared with collagen. Stable expression of constitutively-active mutants of FAK (CD2-FAK) or mitogen-activated protein kinase kinase (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 
1 integrin expression, along with increased activation of FAK, c-Src and ERK, as 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.
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