Prevention of Angiotensin II–Mediated Renal Oxidative Stress, Inflammation, and Fibrosis by Angiotensin-Converting Enzyme 2

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 57; no. 2; pp. 314 - 322
• Main Authors: Zhong, JiuChang, Guo, Danny, Chen, Christopher B, Wang, Wang, Schuster, Manfred, Loibner, Hans, Penninger, Josef M, Scholey, James W, Kassiri, Zamaneh, Oudit, Gavin Y
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.02.2011; Lippincott Williams & Wilkins
• Subjects: Actins - genetics; Actins - metabolism; Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Collagen - genetics; Collagen - metabolism; Cytokines - genetics; Cytokines - metabolism; Female; Fibrosis; Gene Expression - drug effects; Humans; Immunohistochemistry; Inflammation - metabolism; Inflammation - pathology; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth - metabolism; NADPH Oxidases - metabolism; Oxidative Stress - drug effects; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Hypertension; Oxidative stress; hypertension I; Angiotensin I; Peptide hormone; Cardiovascular disease; Inflammation; renal fibrosis; Prevention; Signal transduction; Octapeptide; Fibrosis; Angiotensin II
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.164244

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.5 mg/kg/d) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-1β and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase 1/2 and increase of protein kinase C-α levels. These changes were associated with increased expression of fibrosis-associated genes (α-smooth muscle actin, transforming growth factor-β, procollagen type Iα1) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg/d, intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II–mediated activation of extracellular-regulated kinase 1/2 and protein kinase C pathway and Ang II–mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease.