Abstract
Angiotensin-(1-7) [Ang-(1-7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas(+/+) ) and Mas knockout (Mas (-/-)) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas(+/+) , but not in Mas (-/-) mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1-7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin I / metabolism*
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Animals
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Disease Models, Animal
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Doxorubicin / adverse effects*
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Gene Expression Regulation / drug effects
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology
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Kidney Diseases / chemically induced*
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Kidney Diseases / metabolism*
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Kidney Diseases / pathology
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Kidney Diseases / prevention & control
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Kidney Glomerulus / drug effects
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Kidney Glomerulus / metabolism
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Kidney Glomerulus / pathology
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Kidney Tubules / drug effects
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Kidney Tubules / metabolism
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Kidney Tubules / pathology
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Losartan / administration & dosage
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Losartan / pharmacology
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Mice
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Peptide Fragments / metabolism*
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Peptidyl-Dipeptidase A / metabolism
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Angiotensin, Type 1 / genetics
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Receptor, Angiotensin, Type 1 / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Time Factors
Substances
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AVE 0991
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Angiotensin II Type 1 Receptor Blockers
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Imidazoles
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Peptide Fragments
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptor, Angiotensin, Type 1
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Receptors, G-Protein-Coupled
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Doxorubicin
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Angiotensin I
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Peptidyl-Dipeptidase A
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angiotensin I (1-7)
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Losartan
Grants and funding
Coordenação de Aperfeiçoamento de Pessoal de Nível 445 Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação do Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), the European Union's Sixth Framework Programme (INNOCHEM, project grant LSHB-CT-2005-518167) and the European Community's Seventh Framework Programme [FP7-2007-2013] under grant agreement HEALTH-F4-2011-281608. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.