Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Anti-Inflammatory and Anti-Fibrotic Effect of Angiotensin AT2 Receptors Stimulation or AT1 Receptors Blockade in Scleroderma
Santi1, Francesca, Stroder2, Katja, Rompe2, Franziska, Wieland2, Anja, Artuc3, Metin, Thone-Reineke2, Christa, Malavolta1, Nazzarena
Skin harbours a complete renin-angiotensin-system (RAS). There is evidence for an upregulation of RAS in Scleroderma lesions. Our project aimed at investigating whether pharmacological interference with the RAS (angiotensin AT1 receptor blockade or AT2 receptor stimulation) may be effective in reducing inflammation and fibrosis in a scleroderma murine model.
Female C3/H mice were treated with bleomycin injection (100 ml of a 100 mg/ml solution s.c.) every second day over a period of 4 weeks. Animals were randomised in 4 treatment groups (n=6 each): (i) control group (only vehicle), (ii) Bleomycin; (iii) Bleomycin+ AT1R blocker, Candesartan (0,1 mg/kg bw, s.c. every day); (iv) Bleomycin + AT2R agonist, Compound21 (0,3 mg/kg bw, s.c. every day). Subsequently, tissue samples were collected and analysed for markers of inflammation and fibrosis by real time RT-PCR, Western Blotting and conventional histological staining (HE).
After 4 weeks of Bleomycin injection, histological analysis showed an increased in extracellular matrix primarily within the subdermal layers. This fibrotic reaction was ameliorated both by Compound21 and Candesartan treatment. Histological reduction of fibrosis as a results of Compound21 or Candesartan treatment coincided with a reduced expression of precollagen I&alphaI and TGFb as estimated by Western Blot. Furthermore, Bleomycin elicited an increase in IL-6 and MCP-1 mRNA expression, which could be significantly reduced by Compound21 and Candesartan. Experiments in vitro on human fibroblasts both from healthy donors and from scleroderma patients show results similar to our murine model.
Our data indicate that pharmacological interference with the cutaneous RAS by AT1R blockade or by AT2R stimulation could be a potential therapeutic approach to reduce inflammation and fibrosis in scleroderma and, potentially, in other pathological settings with similar pathomechanism.
To cite this abstract, please use the following information:
Santi, Francesca, Stroder, Katja, Rompe, Franziska, Wieland, Anja, Artuc, Metin, Thone-Reineke, Christa, et al; Anti-Inflammatory and Anti-Fibrotic Effect of Angiotensin AT2 Receptors Stimulation or AT1 Receptors Blockade in Scleroderma [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1066