title: Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity.
abstract: The renin-angiotensin system, especially angiotensin II (ANG II), plays a key role in the development and progression of diabetic nephropathy. ANG 1-7 has counteracting effects on ANG II and is known to exert beneficial effects on diabetic nephropathy. We studied the mechanism of ANG 1-7-induced beneficial effects on diabetic nephropathy in db/db mice. We administered ANG 1-7 (0.5 mg·kg(-1)·day(-1)) or saline to 5-mo-old db/db mice for 28 days via implanted micro-osmotic pumps. ANG 1-7 treatment reduced kidney weight and ameliorated mesangial expansion and increased urinary albumin excretion, characteristic features of diabetic nephropathy, in db/db mice. ANG 1-7 decreased renal fibrosis in db/db mice, which correlated with dephosphorylation of the signal transducer and activator of transcription 3 (STAT3) pathway. ANG 1-7 treatment also suppressed the production of reactive oxygen species via attenuation of NADPH oxidase activity and reduced inflammation in perirenal adipose tissue. Furthermore, ANG 1-7 treatment decreased lipid accumulation in db/db kidneys, accompanied by increased expressions of renal adipose triglyceride lipase (ATGL). Alterations in ATGL expression correlated with increased SIRT1 expression and deacetylation of FOXO1. The upregulation of angiotensin-converting enzyme 2 levels in diabetic nephropathy was normalized by ANG 1-7. ANG 1-7 treatment exerts renoprotective effects on diabetic nephropathy, associated with reduction of oxidative stress, inflammation, fibrosis, and lipotoxicity. ANG 1-7 can represent a promising therapy for diabetic nephropathy.
authors.affiliation: Div. of Cardiology, Dept. of Medicine, Mazankowski Alberta Heart Institute, Univ. of Alberta, 8440 112 St. NW, Edmonton, Alberta, Canada T6G 2B7. gavin.oudit@ualberta.ca.
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.forename: Tharmarajan
authors.initials: T
authors.lastname: Ramprasath
authors.forename: Osama Abo
authors.initials: OA
authors.lastname: Alrob
authors.forename: Jessica
authors.initials: J
authors.lastname: DesAulniers
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000803:Angiotensin I / Q000627:therapeutic use*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000517:prevention & control*; D005355:Fibrosis; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014280:Triglycerides; D000803:Angiotensin I; D008049:Lipase; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C118790:angiotensin I (1-7)
keywords: ATGL; Sirt; angiotensin 1–7; diabetic nephropathy; inflammation; lipotoxicity