Abstract—The relative contribution of circulating versus tissue renin-angiotensin systems to the tissue expression of angiotensin peptides in the kidney remains unresolved. To address this issue, intrarenal and urinary levels of the peptide products of the renin-angiotensin system were assessed in a tissue angiotensin-converting enzyme knockout (tisACE−/−) mouse model. Systolic blood pressure was significantly lower (64.6±3.6 versus 81.4±4.5 mm Hg;P<0.02) and urinary volume was increased (7.25±0.86 versus 2.86±0.48 mL/d;P<0.001) intisACE−/−mice compared with wild-type mice. Intrarenal angiotensin II was 80% lower intisACE−/−mice compared with wild-type mice (5.17±0.60 versus 25.5±2.4 fmol/mg protein;P<0.001). Intrarenal angiotensin I levels also declined by a comparable extent (73%) in thetisACE−/−mice (P<0.01). Intrarenal angiotensin-(1–7) concentrations were similar between the strains, but the ratio of intrarenal angiotensin-(1–7) to angiotensin II and angiotensin I intisACE−/−mice increased 470% and 355%, respectively, compared with wild-type mice. Urinary excretion of angiotensin II and angiotensin-(1–7) were not different, but the excretion of angiotensin I increased 270% intisACE−/−mice (P<0.01). These studies suggest 2 potential mechanisms for the reduction of intrarenal angiotensin II intisACE−/−mice: (1) an attenuated capacity to form angiotensin II by renal angiotensin-converting enzyme and (2) significant depletion of its direct precursor angiotensin I in renal tissue. Sustained intrarenal levels of angiotensin-(1–7) may contribute to chronic hypotension and polyuria intisACE−/−mice, particularly in the context of depleted angiotensin II in the kidney.