Chemico-Biological Interactions 185 (2010) 137–142 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Combination of aspirin with telmisartan suppresses the augmented TGF/smad signaling during the development of streptozotocin-induced type I diabetic nephropathy Shrikant Ramesh Mulay, Anil Bhanudas Gaikwad, Kulbhushan Tikoo ∗ Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), India article info Article history: Received 7 January 2010 Received in revised form 25 February 2010 Accepted 2 March 2010 Available online 9 March 2010 Keywords: Aspirin Telmisartan Nephropathy Inflammation Diabetes abstract Diabetic nephropathy (DN) is the most common indication for the development of end stage renal dis- eases. Inflammation is increasingly seen as the core process in the development of diabetes. Inflammatory markers e.g. NFB (p65 levels), TNF, COX-2 and TGF–smad signaling are the key elements in the development of DN. Renin–angiotensin system suppressors like telmisartan have been used to treat DN, but they are not able to prevent completely because of development of resistance against them. Anti-inflammatory agents like, aspirin acts through both COX dependent and COX independent path- ways. Hence, we thought that combining aspirin with telmisartan will be better therapeutic option in preventing the progression of nephropathy in diabetes. In the present study we studied the effect of this combination on inflammatory markers [COX-2, NFB (p65 levels), TNF], TGF–smad expression in preventing the progression of streptozotocin-induced type I diabetic nephropathy. Treatment of aspirin significantly prevented the progression of nephropathy and inhibited the augmented COX-2, NFB (p65 levels), TNF, and TGF–smad expression. Combination of aspirin with telmisartan resulted in a further decrease in the development of nephropathy and inflammatory markers in comparison to aspirin alone treatment. This is the first report which shows that aspirin in combination with telmisartan is more pro- ficient in the treatment of diabetic nephropathy than any single drug therapy and involves the change in expression of inflammatory markers and TGF–smad signaling. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Diabetic nephropathy (DN) is the most common cause for the development of end stage renal diseases [1]. According to statistics around two million people will require renal replacement ther- apy by 2010 [2]. DN is histologically characterized by mesangial cell expansion, glomerular basement membrane thickening, and glomerulosclerosis [3]. Blood pressure control and reduction of pro- teinuria by means of the renin–angiotensin system suppressors are the most effective therapies to delay progression. Abbreviations: DN, diabetic nephropahty; TNF, tumor necrosis factor-; COX-2, cyclooxygenase-2; TGF, transforming growth factor-; NFB, nuclear fac- tor kappa-light-chain-enhancer of activated B cells; STZ, streptozotocin; Ang II, angiotensin II; ROS, reactive oxygen species; BUN, blood urea nitrogen; TBARS, thiobarbituric acid-reacting substances. ∗ Corresponding author at: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab 160062, India. Tel.: +91 172 2214682–87; fax: +91 172 2214692. E-mail address: tikoo.k@gmail.com (K. Tikoo). Hyperglycemia induced biochemical abnormalities, viz. forma- tion of advanced glycation end products, overactivity of polyol pathway and protein kinase C activation also play a role in the pathogenesis of DN [4]. High glucose elevates angiotensin II (Ang II) production [5]. Ang II mediates the pathophysiological changes in the kidney via AT1 and AT2 receptors. AT1 mediates most of the effects of Ang II viz. vasoconstriction, sodium retention, aldosterone secretion, cell proliferation, etc. [6]. Also being a proinflamma- tory peptide Ang II contributes in the glomerular inflammation and fibrosis [7,8]. It causes activation of nuclear factor kappa B (NFB) (p65 levels), a transcription factor, which further induces the synthesis of other inflammatory cytokines e.g. tumor necrosis factor- (TNF) in the kidney. This might be followed by a recip- rocal process through which NFB (p65 levels) and TNF mutually enhance activation of one another. They further cause transcrip- tion of transforming growth factor- (TGF), interleukins and other inflammatory cytokines [9]. Several pre-clinical and clinical studies have shown that the renin–angiotensin system suppressers ameliorate the progression of DN. Telmisartan, a benzimidazole derivative, is a known anti- hypertensive drug, belongs to the group of Ang II AT1 receptor 0009-2797/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2010.03.008