Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats

Abstract

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.

Introduction

Metabolic syndrome (MS) has evolved into a problem of epidemic proportions in Western countries and associates obesity with numerous other abnormalities, including alterations in glucose metabolism, hyperlipidemia, hypertension and fatty liver (Grundy et al., 2004). Statistics reveal 20–25% of adult population in the world being diagnosed as MS and its presence should therefore be considered as an indicator of long-term risk (Mamikutty et al., 2014). The high prevalence of MS is probably due to the contemporary epidemics of obesity, unhealthy diet, and sedentary lifestyle (Zelber-Sagi et al., 2011).

Many studies assessed the effects of diets containing large amounts of fructose and suggested that fructose consumption tends to produce some metabolic alterations associated with MS including fatty liver, hypertension, insulin resistance and dyslipidemia (Chou et al., 2011, Kretowicz et al., 2011). Fructose has been widely accepted as an animal model for MS that mimics the manifestations afflicting human subjects (Tran et al., 2009).

It has been suggested that activation of the renin–angiotensin system (RAS) is a common feature in patients with MS (Rong et al., 2010). In addition to the exacerbation of hypertension, RAS has been implicated in the etiology of obesity and insulin resistance, providing a pivotal link among all alterations of the MS concerning fatty liver, diabetes and hypertension (Boustany et al., 2004). Nevertheless, multiple lines of evidence indicate that inhibition of RAS improves insulin sensitivity independent of changes in blood pressure (Shiuchi et al., 2004, Mori et al., 2007). In rodents, pharmacological or genetic disruption of RAS prevents weight gain, promotes insulin sensitivity and relieves hypertension (de Kloet et al., 2010).

Telmisartan (TEL), a well-established angiotensin II receptor blocker, is known to improve insulin resistance, decrease triglyceride levels and have anti-inflammatory, anti-oxidant and adipocyte differentiating effects (Yamagishi and Takeuchi, 2005). Furthermore, previous studies had showed that TEL protects against weight gain and hepatic steatosis and provides renal protection in a rat model of MS (Sugimoto et al., 2006, Fujita et al., 2007).

Aliskiren (ALS), a direct renin inhibitor, is a new class of antihypertensive drug that has been demonstrated to reduce blood pressure in essential hypertensive patients (Chou et al., 2011). It was suggested that ALS may lower the production of angiotensin II during the process of chronic liver injury and consequently ameliorates inflammation and fibrosis (Lee et al., 2012). In addition, a previous study had shown that ALS ameliorates MS in rats (Chou et al., 2011).

Despite the consistent demonstration that inhibition of the RAS profoundly reduces MS (Sugimoto et al., 2006, Fujita et al., 2007, Chou et al., 2011), to our knowledge, no studies have compared the relative effects of different modes for pharmacological inhibition of the RAS on the development of MS. Therefore, the aim of the present study was to delineate whether these two pathways of RAS inhibition; angiotensin II receptor blocker (presented as TEL) and renin inhibitor (presented as ALS) differentially improve metabolic and hepatic alterations induced by high fructose diet (FRC) in rats, and to clarify the underlying mechanisms.