The homeostatic function of prostaglandin E₂ (PGE₂) is dependent on a balance of EP receptor-mediated events. A disruption in this balance may contribute to the progression of renal injury. Though PGE₂ excretion is elevated in diabetes, the expression of specific EP receptor subtypes has not been studied in the diabetic kidney. Therefore the purpose of this study was to characterize the expression profile of four EP receptor subtypes (EP_1-4) in 16 wk streptozotocin (STZ) and B6-Ins2^Akita type I-diabetic mice. In diabetics the ratio of kidney weight/body weight was increased 2-fold compared to controls, blood glucose was elevated, but urine albumin was only increased in B6-Ins2^Akita mice. The excretion of PGE₂ and its metabolite was augmented 2-4 -fold as determined by enzyme-immunoassay. Accordingly, renal cyclooxygenases were also increased in diabetic mice, with isoform specific and regional differences in each model. Finally, there is altered EP_1-4 receptor expression in diabetic kidneys, with significant differences between STZ and B6-Ins2^Akita mice (fold control). In STZ mice cortical EP₁ increases by 1.6, EP₃ increases by 2.3, and EP₄ decreases by 0.63; yet in B6-Ins2^Akita mice cortical EP₁ increases by 2.4, but there is a general decrease in the remaining subtypes. Likewise in the STZ medulla EP₃ increases by 3.6, but both EP₁ and EP₃ increase by 5.5 and 1.95 respectively in B6-Ins2^Akita mice. Therefore, knowing the pattern of change in relative EP receptor expression in the kidney could be useful in identifying specific EP targets for the prevention of various components of diabetic kidney disease.