Mesangial cell activation by bacterial endotoxin. Induction of rapid cytoskeletal reorganization and gene expression

Abstract

Cultured glomerular mesangial cells (MC) respond to low concentrations of bacterial endotoxin (ET) by secreting prostaglandins and interleukin-1. To evaluate further the nature of ET-induced mesangial cell activation, the authors evaluated the effects of this agent on MC morphology and cytoskeletal organization. Bacterial ET, in concentrations as low as I ng/ml, induced reversible membrane ruffling, cellular rounding, and extension of many filopodia and lamellopodia. Augmented fluid-phase pinocytosis occurred in parallel, as determined by transmission electron microscopy and tritiated sucrose uptake. These cellular morphologic and functional changes were associated with an extensive, but reversible, depolymerization of actin microfilaments. Actin gene expression was also modified by ET. At 4 to 6 hours after ET exposure, Northern blot analysis showed a twofold to fourfold increase in actin mRNA levels. In situ hybridizations of ET-stimulated cells at the light and electron microscopic levels demonstrated a markedly asymmetric distribution of actin mRNA, which was localized in the cellular periphery at filopodial and lamellopodial extensions, presumably sites of new actin protein synthesis. It is concluded that ET effects on MC are distinct from the nonspecific lytic or 'toxic' actions described for other cell types. Endotoxin induces a global activation of this cell type associated with major changes in membrane structure, cytoskeletal organization, and gene expression, which resemble in many respects the responses to peptide mitogens.