Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease.
Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the (5/6) nephrectomy ((5/6) Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or (5/6) Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT(1) receptor antagonist losartan, MLN plus losartan, or ANG-(1-7) for 4 wk. In (5/6) Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In (5/6) Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. (5/6) Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in (5/6) Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with (5/6) Nx alone, an effect reversed by losartan. Treatment of (5/6) Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after (5/6) Nx. Inhibition of ACE2 in (5/6) Nx mice increases albuminuria via an AT(1) receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after (5/6) Nx. We propose that endogenous ACE2 is renoprotective in CKD.
Dilauro
Marc
M
Division of Nephrology, Departments of Medicine and Cellular and Molecular Medicine, The Ottawa Hospital, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Zimpelmann
Joseph
J
Robertson
Susan J
SJ
Genest
Dominique
D
Burns
Kevin D
KD
D000419:Albuminuria / Q000201:enzymology / Q000503:physiopathology; D000803:Angiotensin I / Q000008:administration & dosage / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002908:Chronic Disease; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006400:Hematocrit; D007093:Imidazoles / Q000008:administration & dosage; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D007444:Inulin / Q000031:analogs & derivatives; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D051379:Mice; D009392:Nephrectomy; D009929:Organ Size; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013997:Time Factors
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D007444:Inulin; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine; C118790:angiotensin I (1-7); D019808:Losartan