Heparan sulfate proteoglycan (HSPG) has been identified as an important determinant of glomerular permselectivity. We have previously reported that glomerular epithelial cells in culture synthesize HSPG, suggesting that in vivo these cells contribute to the HSPG present in the glomerular basement membrane. In this study we examined the effects of dexamethasone on the metabolism of HSPG core protein in cultured glomerular epithelial cells. Dexamethasone caused a dose-dependent and time-dependent increase in the HSPG core protein content of the cells. This effect was not seen with an equimolar concentration of aldosterone, indicating it was selective for dexamethasone. Dexamethasone caused a significant inhibition in 3H-leucine incorporation into de novo synthesized proteins at concentrations that caused maximum increment in the HSPG core protein content. These findings support the interpretation that HSPG core protein is a selective target for dexamethasone. Actinomycin-D completely abrogated the dexamethasone effect on HSPG core protein content, implying that enhanced transcription may be the major mechanism underlying the dexamethasone-induced increment in HSPG core protein content. Our findings suggest that glucocorticoids have important effects on the metabolism of the core protein moiety of heparan sulfate proteoglycan. Furthermore, these data imply that the glucocorticoid-induced amelioration of proteinuria could involve metabolic effects on the local determinants of glomerular permselectivity (e.g., HSPG) in addition to their well-known systemic anti-inflammatory effects.