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

Author:

Zhong JiuChang1,Guo Danny1,Chen Christopher B.1,Wang Wang1,Schuster Manfred1,Loibner Hans1,Penninger Josef M.1,Scholey James W.1,Kassiri Zamaneh1,Oudit Gavin Y.1

Affiliation:

1. From the Division of Cardiology (J.C.Z., D.G., C.B.C., W.W., G.Y.O.), Department of Medicine, Mazankowski Alberta Heart Institute (J.C.Z., D.G., C.b.C., W.W., Z.K., G.Y.O.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria; Division of Nephrology (J.W.S.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology (W.W., Z...

Abstract

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 −1 /d −1 ) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout ( Ace2 −/y ) 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 ½ 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 −1 /d −1 , 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 ½ 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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