Published Online
on February 23, 2004

A more recent version of this article appeared on April 1, 2004

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Submitted on November 25, 2003
Revised on December 11, 2003

Depletion of Tissue Angiotensin-Converting Enzyme Differentially Influences the Intrarenal and Urinary Expression of Angiotensin Peptides

J. Gregory Modrall^*; Javid Sadjadi; K. Bridget Brosnihan; Patricia E. Gallagher; Chun-hua Yu; Gerald L. Kramer; Kenneth E. Bernstein; and Mark C. Chappell

From the Department of Surgery (J.G.M., J.S., C.Y., G.L.K.), University of Texas Southwestern Medical Center, Dallas; Hypertension and Vascular Disease Center (M.C.C., K.B.B., P.E.G.), Wake Forest University School of Medicine, Winston-Salem, NC; and Department of Pathology (K.E.B.), Emory University School of Medicine, Atlanta, Ga.

^* To whom correspondence should be addressed. E-mail: greg.modrall{at}utsouthwestern.edu.

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) in tisACE^-/- mice compared with wild-type mice. Intrarenal angiotensin II was 80% lower in tisACE^-/- 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 the tisACE^-/- 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 in tisACE^-/- 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% in tisACE^-/- mice (P<0.01). These studies suggest 2 potential mechanisms for the reduction of intrarenal angiotensin II in tisACE^-/- 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 in tisACE^-/- mice, particularly in the context of depleted angiotensin II in the kidney.

Key words: angiotensin II • angiotensin I • renin-angiotensin system • mice

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