title: Angiotensin-(1-7) prevents systemic hypertension, attenuates oxidative stress and tubulointerstitial fibrosis, and normalizes renal angiotensin-converting enzyme 2 and Mas receptor expression in diabetic mice.
abstract: We investigated the relationship between Ang-(1-7) [angiotensin-(1-7)] action, sHTN (systolic hypertension), oxidative stress, kidney injury, ACE2 (angiotensin-converting enzyme-2) and MasR [Ang-(1-7) receptor] expression in Type 1 diabetic Akita mice. Ang-(1-7) was administered daily [500 μg/kg of BW (body weight) per day, subcutaneously] to male Akita mice from 14 weeks of age with or without co-administration of an antagonist of the MasR, A779 (10 mg/kg of BW per day). The animals were killed at 20 weeks of age. Age-matched WT (wild-type) mice served as controls. Ang-(1-7) administration prevented sHTN and attenuated kidney injury (reduced urinary albumin/creatinine ratio, glomerular hyperfiltration, renal hypertrophy and fibrosis, and tubular apoptosis) without affecting blood glucose levels in Akita mice. Ang-(1-7) also attenuated renal oxidative stress and the expression of oxidative stress-inducible proteins (NADPH oxidase 4, nuclear factor erythroid 2-related factor 2, haem oxygenase 1), pro-hypertensive proteins (angiotensinogen, angiotensin-converting enzyme, sodium/hydrogen exchanger 3) and profibrotic proteins (transforming growth factor-β1 and collagen IV), and increased the expression of anti-hypertensive proteins (ACE2 and MasR) in Akita mouse kidneys. These effects were reversed by A779. Our data suggest that Ang-(1-7) plays a protective role in sHTN and RPTC (renal proximal tubular cell) injury in diabetes, at least in part, through decreasing renal oxidative stress-mediated signalling and normalizing ACE2 and MasR expression.
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Chao-Sheng
authors.initials: CS
authors.lastname: Lo
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Padda
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Shaaban
authors.initials: S
authors.lastname: Abdo
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chenier
authors.affiliation: †Centre de recherche, Maisonneuve-Rosemont Hospital, Université de Montréal, 5415 boul. de l'Assomption, Montreal, Quebec, Canada, H1T 2M4.
authors.forename: Janos G
authors.initials: JG
authors.lastname: Filep
authors.affiliation: ‡Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, WAC 709, Boston, MA 02114-3117, U.S.A.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: *Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Tour Viger, 900 Saint Denis Street, Montreal, Quebec, Canada, H2X 0A9.
authors.forename: John S D
authors.initials: JS
authors.lastname: Chan
mesh_terms: D000704:Analysis of Variance; D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000652:urine; D000804:Angiotensin II / Q000031:analogs & derivatives; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D006652:Histological Techniques; D006973:Hypertension / Q000209:etiology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000652:urine; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C092006:7-Ala-angiotensin (1-7); D001786:Blood Glucose; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)