(Pro)renin receptor (PRR) is a novel component of the renin-angiotensin system that has been demonstrated to be involved in cardiovascular diseases. Recent research reported that diabetic cardiomyopathy (DCM) may be accompanied by high expression of PRR, indicating that PRR may be a potential therapeutic target for DCM. However, the exact mechanisms of PRR in DCM have not been completely clarified. This study hypothesized that PRR is involved in the pathological progression of DCM and can exacerbate myocardial fibrosis and cardiac dysfunction. Inhibition of PRR expression may alleviate these pathological changes. In this study, experiments were performed in Wistar rats, and experiments were carried out in rat cardiac fibroblasts. After establishing an DCM model, the rats were divided into a control group, DCM group, adenovirus scrambled short hairpin RNA group, and adenovirus PRR short hairpin RNA group to observe further the effects of PRR RNA interference (RNAi) silencing on the pathogenesis of DCM. The results showed that PRR RNAi silencing decreased myocardial fibrosis and improved cardiac function in DCM. The study also observed the effects of PRR RNAi silencing on high glucose stimulated cardiac fibroblasts, and the results showed that PRR RNAi silencing inhibited the expression of type I collagen, type III collagen, and transforming growth factor beta. It was concluded that PRR plays a key role in the pathological progression of DCM and that inhibition of PRR expression achieved by specific PRR RNAi silencing offers a new therapeutic approach for DCM. The underlying mechanisms of these effects may be associated with the ERK signaling pathway and oxidative stress.