Long-Term Administration of Angiotensin (1–7) to db/db Mice Reduces Oxidative Stress Damage in the Kidneys and Prevents Renal Dysfunction

AIMS: The goal of this study was to evaluate the effects of long-term (16 weeks) administration of angiotensin (1–7) [A(1–7)] on kidney function in db/db mice and to identify the protective mechanisms of this therapy. METHODS: db/db mice and heterozygous controls were treated with A(1–7) or vehicle daily, subcutaneously for up to 16 weeks. Kidney injury was assessed by measuring blood flow in renal arteries, plasma creatinine levels, and proteinuria. Effects of treatment on oxidative stress were evaluated by histological staining and gene expression. RESULTS: 16 weeks of daily administration of A(1–7) to a mouse model of severe type 2 diabetes (db/db) prevented the progression of kidney damage. Treatment with A(1–7) improved blood flow in the renal arteries, as well as decreased plasma creatinine levels and proteinuria in diabetic mice. Reduction of oxidative stress was identified as one of the mechanisms of the renoprotective action of A(1–7). Treatment prevented formation of nitrotyrosine residues, a marker of oxidative stress damage. A(1–7) also reduced the expression of two enzymes involved in formation of nitrotyrosine, namely, eNOS and NOX-4. A(1–7) regulated the phosphorylation pattern of eNOS to enhance production of NO in diabetic animals, possibly through the Akt pathway. However, these elevated levels of NO did not result in increased nitrosylation, possibly due to reduced NOX-4 levels. CONCLUSIONS: Long-term administration of A(1–7) improved kidney function and reduced oxidative stress damage in db/db mice.