Ms Marut and Dr. Kavian contributed equally to this work.
Amelioration of Systemic Fibrosis in Mice by Angiotensin II Receptor Blockade
Article first published online: 23 APR 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 5, pages 1367–1377, May 2013
How to Cite
Marut, W., Kavian, N., Servettaz, A., Hua-Huy, T., Nicco, C., Chéreau, C., Weill, B., Dinh-Xuan, A. T. and Batteux, F. (2013), Amelioration of Systemic Fibrosis in Mice by Angiotensin II Receptor Blockade. Arthritis & Rheumatism, 65: 1367–1377. doi: 10.1002/art.37873
- Issue published online: 23 APR 2013
- Article first published online: 23 APR 2013
- Accepted manuscript online: 17 JAN 2013 03:41PM EST
- Manuscript Accepted: 10 JAN 2013
- Manuscript Received: 16 APR 2012
- European Union Seventh Framework Programme. Grant Number: FP7/2007-2013 under grant agreement 215009 RedCat
Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT1) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc.
SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl-induced SSc). Mice were treated daily with irbesartan by oral gavage.
Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and α-smooth muscle actin expression, as well as fibroblast proliferation and H-Ras expression in the skin of mice with HOCl-induced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti–DNA topoisomerase I autoantibodies.
Irbesartan, an AT1 antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl-induced models of systemic fibrosis. Our findings extend the indication of an AT1 antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.