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 current 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 weeks, 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.