Type IV collagen and laminin regulate glomerular mesangial cell susceptibility to apoptosis via beta(1) integrin-mediated survival signals

Postinflammatory scarring is characterized by changes in extracellular matr ix (ECM) composition and progressive loss of normal resident cells. In glom erular inflammation there is now evidence that unscheduled apoptosis (progr ammed cell death) of mesangial and other resident cells may mediate progres sion to irreversible glomerulosclerosis, In the current study we examined t he hypothesis that ECM components may differ in their capacity to support m esangial cell survival by suppression of apoptosis. Using a well-establishe d ill vitro model of mesangial cell apoptosis, we found that collagen IV an d laminin, components of normal mesangial ECM, protected rat mesangial cell s from apoptosis induced by serum starvation and DNA damage, by a beta(1) i ntegrin-mediated, but arg-gly-asp (RGD)-independent mechanism. in contrast, collagen I, fibronectin, and osteonectin/SPARC, which are overexpressed in diseased glomeruli, failed to promote rat mesangial cell survival. However , the survival-promoting effect of collagen IV and laminin was not associat ed with changes in cellular levels of apoptosis regulatory proteins of the Bcl-2 family. These experiments demonstrate that glomerular mesangial cell survival is dependent on interactions with ECM and provide insights into po tential mechanisms by which resident cell loss may occur during acute infla mmation and postinflammatory scarring of the kidney and other organs.