Meprin (MEP) A is a metalloendopeptidase that is present in the renal proximal tubule brush border membrane (BBM) and that co-localizes with angiotensin converting enzyme (ACE). The MEP - chain gene locus on chromosome 18 has been linked to a heightened risk of diabetic nephropathy (DN) in patients with type 2 diabetes. This study evaluated: (1) whether MEP- and MEP- gene and protein expression are altered in db/db mice prior to the onset of DN; and (2) the role of MEP- in the pathogenesis of DN and the impact of the renin-angiotensin system (RAS) on this interaction in two experimental models of diabetes. MEP- and MEP- gene and protein expression were evaluated in db/db mice, 13-14 weeks of age, compared to lean C57BLKS/J littermate animals. A treatment study was then performed in which db/db mice and controls were assigned to one of three groups: control (C) water, no therapy; ACE inhibitor therapy, enalapril (EN)-treated water, 50 mg/L; angiotensin II receptor type 1 blocker (ARB) therapy, losartan (LOS)-treated water, 500 mg/L. Treatment was started at 8 week of age and continued for 52 week. Male Sprague-Dawley rats with diabetes for 52 weeks following a single dose of streptozocin (STZ), 60 mg/kg, were also studied. At 13.5 weeks of age, MEP- and MEP- kidney mRNA abundance and protein expression were significantly lower in db/db mice compared to lean controls, with greater changes in MEP- (P<0.05). In the treatment study, EN ameliorated and LOS exacerbated DN in db/db mice. BBM meprin A enzymatic activity and MEP- protein content were lower in db/db mice versus control non-obese mice at 52 wk (P < 0.02). EN-treated db/db mice showed increased meprin A activity, MEP- content in BBM, decreased urinary MEP- excretion, and enhanced BBM staining for MEP- protein versus C and LOS-treated db/db mice. In non-obese mice, EN and LOS treatment had no effect on MEP- expression. In rats with STZ-induced diabetes for 52 wk, urinary MEP- excretion was increased and meprin A activity and MEP- protein content/mg BBM protein was decreased compared to age-matched control animals (P< 0.05). These results indicate that db/db mice manifest decreased MEP- and MEP- gene and protein expression, prior to the development of overt kidney disease. Moreover, in db/db mice with DN and rats with STZ-diabetes, there was an inverse relationship between renal MEP- content and the severity of the renal injury. Treatment with an ACE inhibitor was more effective than ARB in ameliorating DN in db/db mice, a change that correlated with alterations in urinary excretion and BBM content of MEP-. MEP- may play a role in the pathogenesis of DN and the benefits of ACE inhibitor therapy on the progression of diabetic kidney disease may be related in part to its impact on renal MEP- expression.