Progranulin is a stress-response factor in fibroblasts subjected to hypoxia and acidosis

Abstract

The growth factor progranulin (granulin-epithelin precursor, PC-derived growth factor or acrogranin) regulates proliferation and migration and is implicated in cancer, development, wound repair and neurodegenerative diseases. Under most conditions fibroblasts do not express progranulin in vivo, however its expression is activated following wounding. We hypothesised that progranulin is part of a fibroblast stress response. Fibroblasts in culture were exposed to two physiologically and clinically relevant microenvironmental stresses; hypoxia (1% oxygen) and acidosis, both of which increase progranulin expression. The greatest increases occurred when hypoxia and acidosis were combined. Increased progranulin expression is not a direct response to apoptosis since it occurred under conditions of pH and hypoxia under which cell viability remained high. Low concentrations of progranulin (2 nM) protected fibroblasts from apoptosis induced by extreme acidosis (pH 5.0 and 4.0). We propose that progranulin is part of a fibroblast stress response and is cytoprotective to acidotic stress.

The granulin gene family: from cancer to dementia

“…In other cell types, PGRN is a potent extracellular antiapoptotic factor (16,21,74) and if this is true also for neurons, the loss of half the normal level of PGRN may sensitize the affected neurons to a range of traumatic shocks. Similarly, PGRN has roles in peripheral inflammation.…”

“…Of equal importance to the problems that accrue when PGRN levels are low is what happens to cells with increased exposure to PGRN. Elevated PGRN stimulates proliferation, (8)(9)(10)15,16,28,40) survival, (9,21,74) and motility (9,24,28) of epithelia, fibroblasts, and endothelia. PGRN activates typical growth factor signal transduction pathways such as the phosphorylation of shc and p44/42 mitogen-activated protein kinase (p44/42MAPK) in the extracellular regulated kinase (ERK) pathway as well as phosphatidylinositol 3-kinase (PI3K), protein kinase B/AKT, and the p70 S6 kinase in the PI3K pathway.…”

Modulation of extracellular matrix by nutritional hepatotrophic factors in thioacetamide-induced liver cirrhosis in the rat

“…Additionally, we characterized the expression of progranulin protein and mRNA in cirrhotic and non-cirrhotic livers. Progranulin is a growth factor involved in tumorigenesis, wound repair, neovascularization, inflammation, cell migration and mitosis (7), and cell survival (8). Progranulin expression was high in a mouse model of early diet-induced non-alcoholic steatohepatitis (9), and was recently identified in cultured primary and immortalized hepatic stellate cells (10), but it is not expressed in normal hepatocytes (11).…”

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

“…When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels, and fibroblasts in the wound (13), suggesting that progranulin could function as a chemotactic protein for myeloid-origin cell types and an angiogenic factor. A recent study showed that progranulin is an inducible protein in response to hypoxia or acidosis (14). Taken together, progranulin is an important molecule in inflammatory response and could therefore be involved in chronic subclinical inflammation associated with human obesity and type 2 diabetes.…”