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

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-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 II+ANG-(1-7) coinfusion group; and 4) ANG II+ANG-(1-7)+d-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 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.

• Authors: Ju-Young Moon, Mitsuo Tanimoto, Tomohito Gohda, Shinji Hagiwara, Takahiko Yamazaki, Ikko Ohara, Maki Murakoshi, Tatsuya Aoki, Yuji Ishikawa, Sang-Ho Lee, Kyung-Hwan Jeong, Tae-Won Lee, Chun-Gyoo Ihm, Sung Jig Lim, Yasuhiko Tomino
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 300 Issue 6 Pg. F1271-82 (Jun 2011) ISSN: 1522-1466 [Electronic] United States
• PMID: 21367916 (Publication Type: Journal Article)

Chemical References

• Peptide Fragments
• Reactive Oxygen Species
• Angiotensin II
• Angiotensin I
• NADPH Oxidases
• angiotensin I (1-7)

Topics

• Angiotensin I (metabolism, pharmacology)
• Angiotensin II (metabolism, pharmacology)
• Animals
• Blood Pressure (drug effects, physiology)
• Blotting, Western
• Body Weight (drug effects, physiology)
• Cells, Cultured
• Diabetes Mellitus, Type 2 (metabolism)
• Diabetic Nephropathies (metabolism)
• Immunohistochemistry
• Mesangial Cells (cytology, drug effects, metabolism)
• Mice
• NADPH Oxidases (metabolism)
• Peptide Fragments (metabolism, pharmacology)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Statistics, Nonparametric