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 present 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 wk, 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.

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

“…45 A recent study showed that Ang-(1-7) was able to reduce inflammatory markers in rats with diabetic nephropathy. 46 These data were supported by a study that revealed different molecular approaches for Ang-(1-7)-modulated inflammatory responses in mouse peritoneal macrophages, decreasing IL-6 and TNF-α. 47 A more recent work has demonstrated that high-circulating Ang-(1-7) exerts significant anti-inflammatory effects by decreasing the expression of inflammatory markers in adipose tissue of high-fat-treated rats.…”

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Mas knockout mice lack the antidiuretic action of Ang(1-7) (Santos and Baracho, 1992). Both the anti-and proinflammatory effects of Ang (1)(2)(3)(4)(5)(6)(7) were reported in kidney of Mas knockout mice (Esteban et al, 2009;Singh et al, 2010b;Moon et al, 2011;Bernardi et al, 2012;Giani et al, 2012;Harris, 2012;Chou et al, 2013;Santos et al, 2013).…”

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

“…3, A-D). ANG 1-7-induced attenuation of ROS coupled with the insulin-sensitizing property of ANG 1-7 (12,17) reduced the elevated random blood glucose (Fig. 3E) and plasma TAG (Fig.…”

“…Angiotensin-converting enzyme 2 (ACE2), which cleaves ANG II into ANG 1-7, counterregulates the ACE/ANG II/AT1R axis (11,14,34,43,47). While genetic deletion of the Mas receptor leads to metabolic syndrome and renal injury (36), ANG 1-7 activates signaling pathways in mesangial (26) and proximal tubular cells (15) and attenuates diabetic nephropathy in Zucker diabetic fatty rats (17). Consequently, the ACE2/ANG 1-7/Mas receptor axis represents a promising therapeutic approach to the treatment of diabetic nephropathy.…”