title: Angiotensin-(1-7) attenuates diabetic nephropathy in Zucker diabetic fatty rats.
abstract: Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng·kg(-1)·min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy.
authors.affiliation: Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Giani
authors.forename: Valeria
authors.initials: V
authors.lastname: Burghi
authors.forename: Luciana C
authors.initials: LC
authors.lastname: Veiras
authors.forename: Analía
authors.initials: A
authors.lastname: Tomat
authors.forename: Marina C
authors.initials: MC
authors.lastname: Muñoz
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cao
authors.forename: Daniel
authors.initials: D
authors.lastname: Turyn
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Toblli
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Dominici
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000803:Angiotensin I / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D000803:Angiotensin I; C118790:angiotensin I (1-7)