Beneficial effects of the activation of the angiotensin-(1-7) MAS receptor in a murine model of adriamycin-induced nephropathy

• Published in: PloS one Vol. 8; no. 6; p. e66082
• Main Authors: Silveira, Kátia Daniela, Barroso, Lívia Corrêa, Vieira, Angélica Thomáz, Cisalpino, Daniel, Lima, Cristiano Xavier, Bader, Michael, Arantes, Rosa Maria Esteves, Dos Santos, Robson Augusto Souza, Simões-E-Silva, Ana Cristina, Teixeira, Mauro Martins
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.06.2013; Public Library of Science (PLoS)
• Subjects: ACE2; Activation; Analysis; Angiotensin; Angiotensin I - metabolism; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-converting enzyme 2; Angiotensins; Animal models; Animals; Anthracyclines; Biological activity; Biology; Cardiomyopathy; Diabetes; Disease; Disease Models, Animal; Doxorubicin - adverse effects; Enzymes; Gene Expression Regulation - drug effects; Heart failure; Humans; Hypertension; Imidazoles - administration & dosage; Imidazoles - pharmacology; Injury prevention; Kidney diseases; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Diseases - prevention & control; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - pathology; Losartan - administration & dosage; Losartan - pharmacology; Medicine; Mice; mRNA; Nephropathy; Peptide Fragments - metabolism; Peptidyl-Dipeptidase A - metabolism; Physiological aspects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor mechanisms; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Renal function; Renin; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Time Factors; Transforming growth factors; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066082

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.