Aging nephropathy is a slowly progressive fibrotic process that affects all compartments of the kidney and eventually impairs kidney function; however, little is known about the mechanisms that contribute to this process. These studies examined the epigenetic control of expression of collagen III (Col3a1), a matrix protein that contributes to kidney fibrosis. Using real-time PCR, Western blotting, and chromatin immunoprecipitation assay of kidneys harvested from 4- and 24-mo-old ad libitum-fed F344 rats, we found increased transcription of Col3a1 that was associated with increased RNA polymerase II recruitment despite elevated posttranslational histone modification (H3K27me3) normally associated with gene silencing. A reduction in the density of another repressive modification (H3K9me3) at the Col3a1 locus in aged rats suggests that cooperation between Polycomb- and heterochromatin-mediated systems are required to maintain repression of the Col3a1 gene. These findings demonstrate alterations in epigenetic control of gene expression in association with the fibrosis of aging nephropathy.