INDUCTION OF HIGHLY PROLIFERATIVE PHENOTYPES IN CULTURED GLOMERULAR MESANGIAL CELLS BY BENZO[A]PYRENE ALONE OR IN COMBINATION WITH METHOXAMINE

Recent studies have suggested that aromatic hydrocarbons can initiate glomerular mesangial cell (GMC) injury and contribute to the onset of renal disease, The present studies were conducted to assess the impact of benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon , on the proliferation of GMCs. Challenge of cultured GMCs with BaP (0 .3-30 mu M) for 24 h was associated with concentration-dependent decre ases in DNA synthesis, a response mediated by selective interference w ith early G(1) cell cycle progression. One cycle of sequential treatme nt with 3 mu M BaP for 24 h followed by challenge with 10 mu M methoxa mine (MeoA), a growth-promoting alpha(1)-adrenergic agonist, for an ad ditional 24 h attenuated the inhibitory response elicited by BaP alone . Following three rounds of sequential treatment with BaP and MeoA, GM Cs exposed to BaP alone or BaP/MeoA exhibited enhanced proliferation r ates relative to controls. BaP/MeoA cells acquired the greatest prolif erative enhancement and exhibited unregulated c-jun and c-fos gene exp ression under growth-arrested and serum-stimulated conditions, Marked increases in specific AP-1 binding to a synthetic oligonucleotide were observed upon serum stimulation of quiescent cultures of BaP/MeoA cel ls relative to controls or any of the other treatment groups. These da ta demonstrate that sequential treatment with BaP in combination with MeoA is associated with induction of highly proliferative phenotypes i n GMCs characterized by differential expression of growth-related prot oncogenes. (C) 1995 Academic Press, Inc.