Attenuating effect of angiotensin-(1–7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-A^y/Ta mice

Abstract

-7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1-7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-A y /Ta mice. KK-A y /Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG IIϩANG-(1-7) coinfusion group; and 4) ANG IIϩANG-(1-7)ϩD-Ala 7 -ANG-(1-7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1-7), and A779. The ANG IIϩANG-(1-7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1-7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-B and MAPK signaling activation was also attenuated by ANG-(1-7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-␤1 production in response to ANG II and suggest that ANG-(1-7) may attenuate ANG II-stimulated ROSmediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1-7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.THE RECENT DISCOVERY OF THE renal renin-angiotensin system (RAS) (41), angiotensin-converting enzyme-related carboxypeptidase (ACE2), and ANG-(1-7) has changed the way the RAS is viewed. ANG-(1-7) is present in kidneys at concentrations comparable to ANG II and is associated with vasodilation, modulation of sodium and water transport, and stimulation of nitric oxide synthase (NOS) (7,9,24,34). The effect of ANG-(1-7) on diabetes is still not clear. In a recent study using the streptozotocin-induced diabetic rat model, ANG-(1-7) infusion prevented diabetes-induced abnormal vascular responses to norepinephrine, endothelin-1, and ANG II in the perfused mesenteric bed and renal arteries. This study also reported decreased urinary albumin excretion in response to ANG-(1-7) (6, 7, 13). Another study in the same streptozotocin-induced diabetic rat model showed that chronic injection of ANG-(1-7) accelerated diabetic renal injury (36). In db/db mice, glomerular expression of ACE2 was increased, and ACE2 inhibitor use showed increased glomerular staining for fibronectin and an extracellular matrix protein (42). However, there have been no studies on the direct effect of ANG-(1-7) on ANG II-induced diabetic glomerular changes.

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).…”

Role of the TNF pathway in the progression of diabetic nephropathy in KK-Aymice

“…Measurement of NF-B activation. Nuclear extracts were obtained from renal cortices using a Nuclear Extract Kit (Active Motif, Tokyo, Japan) as previously described (20,35). NF-B activation was measured using an NF-B Transcription Factor Assay Kit (Active Motif) according to the manufacturer's recommendations.…”

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…Besides its physiological relevance for kidney homeostasis, the ACE2/Ang-(1-7)/Mas axis also has an important and controversial role in renal diseases, acting as a renoprotective (Oudit et al 2006, 2010, Soler et al 2007, Pinheiro et al 2009, Burns et al 2010, Dilauro et al 2010, Zhang et al 2010, Giani et al 2011, Liu et al 2011b, Moon et al 2011, Stegbauer et al 2011, Zhong et al 2011, Barroso et al 2012, Kim et al 2012, Nadarajah et al 2012 or a proinflammatory (Esteban et al 2009, Velkoska et al 2011 agent. Briefly, Pinheiro et al (2009) reported that mice with genetic deletion of Mas developed renal dysfunction with an increase of glomerular tuft diameter and enhancement of fibronectin and collagen IV and III deposition, besides an increase of AT 1 and TGF-b expression.…”