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

Abstract

ANG-(1–7) 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-Ay/Ta mice. KK-Ay/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1–7) coinfusion group; and 4) ANG II+ANG-(1–7)+d-Ala7-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 II+ANG-(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-κB 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-β1 production in response to ANG II and suggest that ANG-(1–7) may attenuate ANG II-stimulated ROS-mediated 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.