Expression of acute-phase response proteins in retinal Muller cells in diabetes

PURPOSE. To characterize the whole spectrum of gene expression changes induced by diabetes in retinal Muller glial cells. METHODS. Muller cells were isolated from the retina of streptozotocin-diabetic and age-matched control rats by gradient centrifugation and immediately processed for RNA isolation. The gene expression profile of Muller cells was studied with the GeneChip Rat Genome oligonucleotide array (Affymetrix, Santa Clara, CA). The upregulation of acute-phase proteins in the retina of diabetic rats was confirmed by Northern and Western blot analyses. Real-time-RT-PCR was used to study the retinal expression of inflammatory cytokines. RESULTS. Gene expression profiling identified 78 genes as differentially expressed in diabetic Muller cells. One third of these genes were associated with inflammation, including a large cluster (18% of the differentially expressed genes) of acute-phase response proteins: alpha(2)-macroglobulin, ceruloplasmin, complement components, lipocalin-2, metallothionein, serine protease inhibitor-2, transferrin, tissue inhibitor of metalloproteases-1, transthyretin, and the transcription factor C/EBPdelta. Northern and Western blot analyses confirmed the upregulation of alpha(2)-macroglobulin and ceruloplasmin in the diabetic retina, but not in the cerebral cortex and liver of the same animals. The acute-phase response of Muller cells in diabetes was associated with upregulation of interleukin (IL)-1beta in the retina. CONCLUSIONS. Muller cells acquire a complex and specific reactive phenotype in diabetes characterized by the induction of acute-phase response proteins and other inflammation-related genes. The concomitant upregulation of IL-1beta in the retina of diabetic rats points to this cytokine as a possible mediator of the acute-phase response mounted by Muller cells in diabetes.