Diabetic nephropathy (DN) is a common type of end-stage renal disease and glomerular mesangial cells (GMCs) are widely used as a cell model for DN. This study firstly investigated the inhibitory effects of the Apostichopus japonicus and Acaudina leucoprocta hydrolysates on cellular growth under high-glucose treatment, better inhibitory effect of A. japonicus hydrolysate was observed compared to that of A. leucoprocta hydrolysate. Subsequently, the global transcription profiles obtained via microarray analysis showed that 6 070 and 7 015 genes were identified in the A. japonicus and A. leucoprocta groups compared with the model group, respectively. Among them, transcriptions of the slc30a4, slc35d1, tppp3, tp53inp1, bcl-2, apaf1, alox12b and adrala genes were restored from the levels of the model group to those of the control group, contributed to cell mitosis and proliferation in both treatment groups. In addition, other apoptosis-related genes, such as bcl-6, clu, foxo3 and aktl, showed opposite trends between two groups, which might cause the difference in inhibitory effect. We preliminarily proposed that the regulation effects of A. japonicus and A. leucoprocta on the genes involved in cellular mitosis, proliferation and apoptosis, might contribute to their inhibitory activity on GMCs under high-glucose environment.