Prolylcarboxypeptidase (PRCP) regulates plasma prekallikrein/high molecular weight kininogen/bradykinin axis. It also modulates angiotensin II (Ang II), angiotensin III (Ang III), and alpha-melanocyte stimulating hormone (α-MSH) physiological effects. Study suggests that increased plasma PRCP level is associated with cardiovascular risk factors, such as atherosclerosis, inflammation, and diabetes. Since expression pattern of PRCP in Zucker diabetic fatty (ZDF) rat vascular tissue remain unproved, we aimed to study its expression in the heart and kidney. The purpose of the present study was also to obtain systemic information of inflammation status with regard to PRCP expression and function in a high-fat diet (HFD)- fed ZDF rats. The ZDF rats were divided into 2 groups, which were fed a high-fat diet for 16 weeks or 32 weeks. Differential expression and pathological significance of PRCP expression during the consecutive stages of renal disease development were identified. After 16 weeks, ZDF rats exhibited early transiently altered PRCP expression in the heart and kidneys. After 32 weeks, ZDF rats showed continuously altered expression in PRCP and inflammatory markers, which was linked to severe hyperglycemia and nephropathy. Altered expression of PRCP associated with inflammatory mediators was illustrated to be functionally relevant. In further support of an important role of PRCP, we found PRCP protein to be highly elevated in rat plasma and in human plasma and the anti-diabetic agents reversed it. These findings indicate that impairment of tissues within the cardiovascular system influences PRCP expression and suggest that pathogenic mechanisms of deregulated PRCP expression warrant further investigation.