We previously reported that endoplasmic reticulum (ER) stress induced by glucolipotoxicity and homeostatic inflammation through intraglomerular cellular crosstalk may play an important role in the progression of diabetic kidney disease. Crosstalks of mesangial cell (MC)-endothelial cell (EC) or podocyte-EC have been established, whereas cross-communication between podocytes and MCs is still scarce. Moreover, involvement with these consequences in podocyte injury still remains unclear. Cluster analyses were performed using cDNA microarray data set of isolated glomeruli from two distinct diabetic mouse models. By use of DAVID bioinformatics resources, commonly increased or decreased genes to both models were extracted, and made integrative analyses. Next, we conducted quantitative PCR array focused on ER stress associated genes. Using cultured mouse podocytes (MPC5) and mouse macrophages stimulated with mesangial cell-cultured medium (MC-sup) under high-glucose condition (HG), we evaluated podocyte-specific responses compared to those in macrophages. Further evaluations of ER stress and apoptotic responses of MPC5 stimulated with MC-sup were made by Western blotting, real-time PCR and TUNEL staining. The effects of an ER-associated degradation (ERAD) inhibitor Eeyarestatin I (EerI) in MPC5 and db/db mice were also examined. Commonly increased or decreased genes in both DM models were associated with apoptosis (enrichment score 3.03), inflammation (3.03), and energy metabolism (1.24), suggesting ER stress as a potential factor. Pathway-focused PCR array analysis revealed that genes related to ERAD pathway (xbp1, erp44, ero1-lb, derlin) were suppressed, but apoptotic pathway was enhanced in podocytes stimulated with HG MC-sup. Besides, these responses were also observed in isolated diabetic glomeruli. In vitro, IRE1α and spliced XBP1 were suppressed in podocytes by HG MC-sup, although apoptosis evaluated by TUNEL-staining, Bax (and Bax/Bcl-2 ratio), ATF6 and CHOP was markedly increased. These results were augmented by HG MC-sup compared to MC-sup under low-glucose condition. Other types of cells, such as proximal tubular cells or macrophages, did not show any similar responses. Of note, treatment with EerI recapitulated similar responses, namely suppressed IRE1α, spliced XBP1 and Derlin-2 in podocytes. In vivo, administration of EerI tended to exacerbate albuminuria in db/db mice. It is recently reported that ERAD pathway may play important roles in the maintenance of podocytes to avoid ER stress in several glomerular diseases including diabetic kidney disease. In the present study, we firstly reveal that intraglomerular crosstalk between MCs and podocytes inhibits normal ERAD processes, potentially causing podocyte injury in diabetic conditions.