The combination of diabetes and renal failure is associated with accelerated cardiomyopathy, but the molecular mechanisms of how renal failure drives diabetic heart disease remain elusive. We speculated that the metabolic abnormalities of renal failure will affect the epigenetic control of cardiac gene transcription and sought to determine the histone H3 modification pattern in hearts of type 2 diabetic mice with several degrees of renal dysfunction. We studied the histone H3 modifications and gene expression in the heart of 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age, which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Western blotting of hearts from uninephrectomized db/db mice with glomerulosclerosis, albuminuria, and reduced glomerular filtration rate revealed increased acetylation (K23 and 9), phosphorylation (Ser 10), dimethylation (K4), and reduced dimethylation of (K9) of cardiac histone H3 as compared with db/db mice with normal renal function or nondiabetic wild-type mice. This pattern suggests alterations in chromatin structure that favor gene transcription. In fact, hearts from uninephrectomized db/db mice revealed increased mRNA expression of multiple cardiomyopathy-related genes together with cardiomyocyte hypertrophy. These data suggest that renal failure alters cardiac histone H3 epigenetics, which foster cardiomyocyte hypertrophy in type 2 diabetes.