Glomerular epithelial cells (GECs) are intrinsic components of the kidney glomerulus and are in contact with extracellular matrix (ECM). Under normal conditions, there is little turnover of GECs, but in glomerular injury, apoptosis and proliferation of GECs, and expansion of ECM may lead to sclerosis and impaired glomerular function and/or permselectivity. In order to better understand how adhesion to ECM modulates GEC survival and proliferation, we monitored the activation of the intracellular signaling pathways activated by adhesion to ECM (collagen), along with their coordinate modulation of the growth factor signaling pathways. Adhesion to collagen resulted in the activation of a focal adhesion kinase (FAK)/Src/Grb2 complex, thus activating extracellular signal-regulated kinase (ERK), possibly within focal adhesions. The ERK pathway was necessary to promote survival and growth factor-dependent proliferation. ECM-induced ERK activation was also necessary to achieve and maintain a cortical F-actin structure. There appeared to be a reciprocal relationship between collagen-induced cortical F-actin assembly and collagen-dependent survival signaling, including ERK activation. Moreover, maintenance of the cortical F-actin architecture was associated with increased turnover of inositol phospholipids. Analogous signals for GEC survival are activated in experimental focal segmental glomerulosclerosis (FSGS) in vivo. These studies will provide insights into novel therapeutic approaches to preserving intact glomerular permselectivity.
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