Depletion of tissue angiotensin-converting enzyme differentially influences the intrarenal and urinary expression of angiotensin peptides.
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.
Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9157, USA. greg.modrall@utsouthwestern.edu
J Gregory
JG
Modrall
Javid
J
Sadjadi
K Bridget
KB
Brosnihan
Patricia E
PE
Gallagher
Chun-hua
CH
Yu
Gerald L
GL
Kramer
Kenneth E
KE
Bernstein
Mark C
MC
Chappell
D000803:Angiotensin I / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000804:Angiotensin II / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure; D002268:Carboxypeptidases / Q000096:biosynthesis / Q000235:genetics; D004231:Diuresis; D005786:Gene Expression Regulation; D007022:Hypotension / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010446:Peptide Fragments / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D011141:Polyuria / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000502:physiology*
D010446:Peptide Fragments; D012333:RNA, Messenger; D000804:Angiotensin II; D000803:Angiotensin I; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)