Endocrine Pharmacology Does telmisartan prevent hepatic fibrosis in rats with alloxan-induced diabetes? ☆ Zekai Halici a , Habip Bilen b , Fatih Albayrak c , Abdullah Uyanik d , Ramazan Cetinkaya d , Halis Suleyman a , Osman Nuri Keles e , Bunyami Unal e, ⁎ a Department of Pharmacology, Ataturk University School of Medicine, Erzurum, Turkey b Internal Medicine, Division of Endocrinology and Metabolism, Ataturk University School of Medicine, Erzurum, Turkey c Internal Medicine Division of Gastroenterology, Ataturk University School of Medicine, Erzurum, Turkey d Internal Medicine Division of Nephrology, Ataturk University School of Medicine, Erzurum, Turkey e Departments of Histology and Embryology, Ataturk University School of Medicine, Erzurum, Turkey abstract article info Article history: Received 28 December 2008 Received in revised form 15 April 2009 Accepted 20 April 2009 Available online 3 May 2009 Keywords: Angiotensin Diabetes mellitus Liver Stereology TGF-β Background/aims: This study evaluated the effect of telmisartan on the livers of diabetic rats and also aimed to determine the hepatic distribution and role of transforming growth factor β (TGF-β) in diabetes-related hepatic degeneration while taking into account the possible protective effects of telmisartan. Methods: Fifteen adult male rats were used and divided into three groups: the non-diabetic healthy group, alloxan- induced diabetic control group, and the alloxan-induced diabetic telmisartan group. The non-diabetic healthy group and the diabetic control group were exposed to saline for 30 days, while the group treated with diabetic drugs was orally administered telmisartan for 30 days (10 mg/kg/day). At the end of the experiment, the rats were sacrificed and the livers were dissected and transferred into the fixation solution. The livers were then evaluated using stereological and histopathological methods. Results: Our study of the numerical density of hepatocytes shows a significant difference between the diabetic control group and diabetic rats treated with telmisartan. Immunohistochemical staining for TGF-β in liver sections of the diabetic rats treated with telmisartan showed no immunoreactivity. The diabetic control group was determined to be strongly immunoreactive to TGF-β. Conclusion: Results suggest that telmisartan may reduce type-I diabetes mellitus-induced hepatic injury by suppressing activated hepatic stellate cells through concomitant TGF-β1 down-regulation. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Many clinical trials have proven that using some antihypertensive drug groups such as angiotensin receptor type I (AT 1 receptor) blockers to reduce blood pressure decreases the complications of hypertension (Bloch and Basile, 2004). Unlike other antihypertensive drugs, angiotensin receptor type I blockers are beneficial for reducing nephropathy, coronary vascular disease, and paralysis in diabetic patients. No longer, angiotensin AT 1 receptor blocker usage in hypertensive patients with heart failure, renal failure, and especially diabetes became an inevitable indication. Nevertheless, though all angiotensin AT 1 receptor blockers are thought to be clinically beneficial, there is increasing evidence that each type does not exert the same benefits, especially in chronic treatment (Miura et al., 2005). Telmisartan, a common angiotensin AT 1 receptor blocker, shows antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ)(Benson et al., 2004). The structural similarities between telmisartan and pioglitazon, the PPAR-γ ligand, have been detailed in previous studies. In a study performed according to these findings at physiological concentrations, it was found that of angiotensin AT 1 receptor blockers, only telmisartan caused significant PPAR-γ activation (Benson et al., 2004). Furthermore, telmisartan is known to cause the following in vitro responses characteristic of PPAR-γ activation: adiposity differentiation and selective organization of the genes that play a role in lipid and carbohydrate metabolism (Benson et al., 2004). Diabetes mellitus is one of the most prevalent chronic diseases in the world. Chronic liver disease and diabetes mellitus can co-exist in a single individual, and the liver is a frequent site of unrecognized injury in diabetes mellitus patients. The mortality rate in diabetes mellitus patients is generally not due to classical diabetes-related complications (micro and/or macro vascular complications), but rather to an increased risk of hepatocellular failure via nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis. Chronic liver injury is typically silent in its progression, and the presence of liver disease in patients with progressively worsening insulin resistance may not be European Journal of Pharmacology 614 (2009) 146–152 ☆ This research was conducted in the Laboratory of Pharmacology at Ataturk University, School of Medicine, 25240 Erzurum/Turkey and the Laboratory of Histology and Embryology, School of Medicine, at Ataturk University, 25240 Erzurum/Turkey. None of the authors has a commercial interest, financial interest, and/or other relationship with manufacturers of pharmaceuticals, laboratory supplies, and/or medical devices or with commercial providers of medically related services. ⁎ Corresponding author. Tel.: +90 4422316590; fax: +90 4422360968. E-mail address: bunyamiunal@gmail.com (B. Unal). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.04.042 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar