Telmisartan treatment targets inflammatory cytokines to suppress the pathogenesis of acute colitis induced by dextran sulphate sodium Somasundaram Arumugam a,1 , Remya Sreedhar a,1 , Rajarajan A. Thandavarayan a,b , Vijayasree V. Giridharan c , Vengadeshprabhu Karuppagounder a , Vigneshwaran Pitchaimani a , Mst. Rejina Afrin a , Shizuka Miyashita a , Mayumi Nomoto a , Meilei Harima a , Hiroshi Suzuki a , Takashi Nakamura a , Masahiko Nakamura d , Kenji Suzuki e , Kenichi Watanabe a,⇑ a Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956 8603, Japan b Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA c J.K.K. Nattraja College of Pharmacy, Natarajapuram, Komarapalayam, Namakkal 638183, Tamil Nadu, India d Department of Cardiology, Yamanashi Prefectural Central Hospital, Kofu, Yamanashi, Japan e Department of Gastroenterology and Hepatology, Niigata University of Graduate School of Medical and Dental Sciences, Niigata 951 8510, Japan article info Article history: Received 24 December 2014 Received in revised form 25 March 2015 Accepted 25 March 2015 Available online xxxx Keywords: Telmisartan Renin angiotensin system Acute colitis Apoptosis Inflammatory cytokines abstract The renin angiotensin system (RAS) is essential for the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Recent studies have demonstrated a locally expressed RAS in various tissues of mammals, which is having pathophysiological roles in those organ system. Interestingly, local RAS has important role during the inflammatory bowel disease pathogenesis. Further to delineate its role and also to identify the potential effects of telmisartan, an angiotensin recep- tor blocker, we have used a mouse model of acute colitis induced by dextran sulphate sodium. We have used 0.01 and 5 mg/kg body weight doses of telmisartan and administered as enema to facilitate the on- site action and to reduce the systemic adverse effects. Telmisartan high dose treatment significantly reduced the disease activity index score when compared with the colitis control mice. In addition, oxida- tive stress and endoplasmic reticulum stress markers expression were also significantly reduced when compared with the colitis control mice. Subsequent experiments were carried out to investigate some of the mechanisms underlying its anti-inflammatory effects and identified that the mRNA levels of pro-inflammatory cytokines such as tumour necrosis factor a, interleukin 1b, interleukin 6 and monocyte chemoattractant protein 1 as well as cellular DNA damage were significantly suppressed when compared with the colitis control mice. Similarly the apoptosis marker proteins such as cleaved caspase 3 and 7 levels were down-regulated and anti-apoptotic protein Bcl2 level was significantly upregulated by telmi- sartan treatment. These results indicate that blockade of RAS by telmisartan can be an effective therapeu- tic option against acute colitis. Ó 2015 Elsevier Ltd. All rights reserved. 1. Introduction Inflammatory bowel diseases (IBD) are persistent, perennial diseases, which constitute pertinent clinical problems in day-to- day medical practice. In spite of vast advances in recognition of fac- tors underlying these diseases, the origination and development of non-specific colitis and similar inflammatory gastrointestinal diseases lasts uncertain [1]. With the prevalence of IBD and its associated risk for development of colorectal cancer, it is important to prevent and treat IBD. But, because of the complexity of etiology and potentially serious adverse effects, options for its treatment are relatively limited [2]. Although IBD are multifactorial diseases, involving genetic, immunological and environmental factors, the onset is characterised by an autoimmune inflammation that causes excessive production of pro-inflammatory cytokines to damage intestinal mucosa [3]. The renin angiotensin system (RAS) is classically known for con- trolling the blood pressure however, recently it is also considered as an inflammation regulator. Apart from the systemic RAS, tissue intrinsic RASs have been identified in various tissues and reported http://dx.doi.org/10.1016/j.cyto.2015.03.017 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1, Higashijima, Akiha Ku, Niigata 956 8603, Japan. Tel.: +81 250255267; fax: +81 250255021. E-mail address: watanabe@nupals.ac.jp (K. Watanabe). 1 Authors contributed equally. Cytokine xxx (2015) xxx–xxx Contents lists available at ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Please cite this article in press as: Arumugam S et al. Telmisartan treatment targets inflammatory cytokines to suppress the pathogenesis of acute colitis induced by dextran sulphate sodium. Cytokine (2015), http://dx.doi.org/10.1016/j.cyto.2015.03.017