An organ culture system was used to study the effect of D-glucose on embryonic kidneys, and to delineate the mechanism(s) relevant to their dysmorphogenesis. Metanephroi were cultured in the presence of 30 mM D-glucose. A notable reduction in the size and population of nephrons was observed. Ureteric bud branches were rudimentary and the acuteness of their tips, the site of nascent nephron formation, was lost. Metanephric mesenchyme was atrophic, had reduced cell replication, and contained numerous apoptotic cells. Competitive reverse transcriptase-PCR analyses and immunoprecipitation studies indicated a decrease in expression of heparan sulfate proteoglycan (perlecan). Status of activated protein-2 was evaluated since its binding motifs are present in the promoter region of the perlecan gene. Decreased binding activity of activated protein-2, related to its phosphorylation, was observed. D-glucose-treated explants also had reduced levels of cellular ATP. Exogenous administration of ATP restored the altered metanephric morphology and reduced [35S]sulfate-incorporated radioactivity associated with perlecan. The data suggest that D-glucose adversely affects the metanephrogenesis by perturbing various cellular phosphorylation events involved in the transcriptional and translational regulation of perlecan. Since perlecan modulates epithelial/mesenchymal interactions, its deficiency may have led to the metanephric dysmorphogenesis and consequential atrophy of the mesenchyme exhibiting accelerated apoptosis.