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 matrix (ECM) composition and progressive loss of normal resident cells. In glomerular inflammation there is now evidence that unscheduled apoptosis (programmed cell death) of mesangial and other resident cells may mediate progression to irreversible glomerulosclerosis. In the current study we examined the hypothesis that ECM components may differ in their capacity to support mesangial cell survival by suppression of apoptosis. Using a well-established in vitro model of mesangial cell apoptosis, we found that collagen IV and laminin, components of normal mesangial ECM, protected rat mesangial cells from apoptosis induced by serum starvation and DNA damage, by a beta(1) integrin-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 associated 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 potential mechanisms by which resident cell loss may occur during acute inflammation and postinflammatory scarring of the kidney and other organs.
Mooney
A
A
Division of Renal and Inflammatory Disease, Department of Medicine, University Hospital, Nottingham, United Kingdom.
Jackson
K
K
Bacon
R
R
Streuli
C
C
Edwards
G
G
Bassuk
J
J
Savill
J
J
D000818:Animals; D017209:Apoptosis; D018929:Cell Culture Techniques; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism / Q000502:physiology*; D005047:Etoposide / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D005920:Glomerular Mesangium / Q000378:metabolism*; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D015676:Osteonectin / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494774:Bak1 protein, rat; C494813:Bcl2l1 protein, rat; D005353:Fibronectins; D019012:Integrin beta1; D007797:Laminin; D008565:Membrane Proteins; D015676:Osteonectin; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D005047:Etoposide; D003094:Collagen