Angiotensin-(1-7) ameliorates renal damage in Zucker diabetic rats.

DOMINICI FP; MUÑOZ MC; TOBLLI JE; GIANI JF

Ventura, Los Angeles, California

Congreso; Gordon Research Conference on Angiotensin; 2012

Gordon Research Conference

INTRODUCTION: Ang-(1-7) is associated with enhancement of insulin action at glucose and lipid metabolism. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. Thus, in the current study we evaluated the renal effects of chronic Ang-(1-7) treatment in Zucker diabetic fatty rats (ZDF),  an animal model of type 2 diabetes, obesity, hypertension, dislypemia and nephropathy. METHODS: 12 male ZDF 4 months of age and their respective controls (Lean Zucker rats; LZR) were used for this study. The protocol involved study of three groups: 1) control LZR-saline administered group; LZR-saline 2) ZDF-saline group and 3) ZDF + Ang-(1-7) infusion group. All groups of animals were fed ad libitum. For 2 weeks, 4 animals from each group where implanted subcutaneous osmotic pumps that delivered either saline or Ang-(1-7) (100 ng·kg-1· min-1). Determinations of body weight, glycemia, trygliceridemia, insulinemia, creatinine clearance, proteinuria and systolic blood pressure were performed both at the beginning and at the end of the treatment. Renal interstitial fibrosis (Sirius Red) as well as the renal levels of Ang II, IL-6, and ED-1 were determined by means of immunohistochemistry and confirmed by immunoblotting. Tissue parameters of oxidative stress (glutathione, T-BARS) as well as renal activity of antioxidant enzymes [superoxide dismutase (SOD) and catalase] were also determined.  RESULTS AND CONCLUSION. Ang-(1-7) induced a significant reduction in trygliceridemia in ZDF. SBP was also significantly reduced after Ang-(1-7) treatment. At the end of the study, ZDF-saline rats exhibited a large increase in renal fibrosis. This alteration was associated with an elevation of IL-6, and ED-1 in renal cortex as detected by inmunohistochemisty and immunoblotting. Ang-(1-7) treatment attenuated renal damage by inducing a significant reduction of renal fibrosis in ZDF, concomitant with a decrease in the renal immunostaining of IL-6 and ED-1 to values not significantly different to those displayed by LZR, implying a renoprotective role. This attenuation of nephropathy proceeded with a concomitant decrease in oxidative stress and an increase in the activity of both renal SOD and catalase. Ang II levels remained unchanged in ZDF-. CONCLUSIONS. Chronic Ang-(1-7) treatment exerts a renoprotective effect in ZDF together associate with an improvement of the metabolic profile, a reduction of SBP and oxidative stress in this tissue. This suggests that the ACE2-ANG-(1-7)-Mas receptor axis appears as a novel target for treatment of type 2 diabetic nephropathy.