Cardiac
Protective effects of naringenin in cardiorenal syndrome

https://doi.org/10.1016/j.jss.2016.03.003Get rights and content

Abstract

Background

Cardiorenal syndrome is a complicated and bidirectional interrelationship between the heart and kidneys. Naringenin (NG) is a naturally occurring flavonoid possessing various biological and pharmacological properties.

Materials and methods

We tested whether NG could improve cardiac and renal function in a rat model of cardiorenal syndrome.

Results

The results showed that NG-attenuated cardiac remodeling and cardiac dysfunction in rats with cardiorenal syndrome, as evidenced by decrease of left ventricle weight (LVW), increase of body weight (BW), decrease of LVW/BW, decrease of concentrations of serum creatinine, blood urea nitrogen, type-B natriuretic peptide, aldosterone, angiotensin (Ang) II, C-reactive protein, and urine protein, increase of left ventricular systolic pressure and falling rates of left ventricular pressure (dp/dtmax), and decrease of left ventricular diastolic pressure, left ventricular end-diastolic pressure, and −dp/dtmax. NG significantly inhibited the increase of lipid profiles including low-density lipoprotein, TC, and TG in rats. In addition, NG significantly inhibited the increase of cardiac expression of IL-1β, IL-6, and interferon γ. Moreover, NG decreased malonaldehyde level, increased superoxide dismutase activity and glutathione content in rats, and increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and catalytic subunit of γ-glutamylcysteine ligase (GCLc) in rats and Ang II-treated cardiac fibroblasts. Inhibition of Nrf2 and glutathione synthesis significantly suppressed NG-induced decrease of ROS level. Inhibition of Nrf2 markedly suppressed NG-induced increase of GCLc expression in Ang II-treated cardiac fibroblasts.

Conclusions

The data provide novel options for therapy of patients and new insights into the cardioprotective effects of NG in cardiorenal syndrome.

Introduction

The heart has a complicated and bidirectional interrelationship with the kidneys.1 Impairment of one organ could influence the other one, which in turn results in damage of both organs. This phenomenon is defined as cardiorenal syndrome.1 Cardiovascular morbidity is considered to be the major cause of death among those patients with impaired renal function.2, 3 In turn, myocardial infarction has been reported to result in injury of renal function.4 Therefore, impairment of renal and cardiovascular function forms a vicious cycle through cardiorenal interaction, leading to increase of morbidity and mortality in patients with cardiovascular and renal diseases. Numerous literature has suggested that the renin-angiotensin-aldosterone system, sympathetic nervous system, endothelial dysfunction, oxidative stress, and inflammation are involved in cardiorenal syndrome.5, 6, 7, 8, 9, 10

Naringenin (NG) is a naturally occurring flavonoid which is widely distributed in grapefruit, lemon, and tomato.11 NG possesses various biological and pharmacologic properties, including antioxidant, anti-inflammatory, antithrombotic, anticarcinogenic, antidiarrheal, and antiulcer activities. In the last decade, several studies have shown that NG exhibits cardiovascular and renal protective effects. Subburaman et al. showed that NG protected against doxorubicin-induced cardiotoxicity in a rat model.12 Karuppagounder et al. found that NG-ameliorated daunorubicin-induced nephrotoxicity through inhibition of inflammation.13 However, whether NG could improve the outcomes of cardiorenal syndrome is unclear.

In the present study, we sought to assess whether NG could improve cardiac and renal function in a rat model of cardiorenal syndrome. We found that NG attenuated cardiac remodeling and cardiac dysfunction in rats with cardiorenal syndrome. NG decreased lipid profiles, inhibited cardiac inflammation, and reduced oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) and/or catalytic subunit of γ-glutamylcysteine ligase (GCLc)-regulated glutathione (GSH) synthesis contributed to NG-induced antioxidant effects and thus the cardioprotective effects against cardiorenal syndrome.

Section snippets

Animal treatment

All the experimental procedures were approved by the Animal Ethnics Committee of the Yan'an University. All experiments were carried out in accordance with the approved guidelines. 80 Male Sprague Dawley rats (180-220 g) were purchased from Laboratory Animal Centre of Yan'an University. The animals were housed under conditions of controlled temperature (23 ± 2°C) and humidity (60%) with 12-h light and/or dark cycles.

Rat model of cardiorenal syndrome was established as previously reported.14, 15

NG attenuated cardiac remodeling and dysfunction in rats with cardiorenal syndrome

The administration of NG significantly and dose dependently decreased LVW, increased BW, and decreased LVW/BW, compared with that of rats with cardiorenal syndrome (Table 1). The results indicated that NG attenuated cardiac remodeling in rats with cardiorenal syndrome. Concentration of Scr in rats with cardiorenal syndrome was decreased from 88.7 ± 9.8 μmol/L to 72.1 ± 8.5 μmol/L and 59.6 ± 9.9 μmol/L by low dose of NG and high dose of NG (P = 0.006), respectively (Table 2). NG significantly

Discussion

Flavonoids are naturally occurring compounds that have a wide variety of biological properties. NG, a flavanone, is one of the major antioxidants that are present in citrus fruits. Numerous literature has shown that NG possesses cardio and renal protective effects in vivo and in vitro.12, 19, 20, 21, 22 Those findings provide a possibility that NG may have beneficial effects for cardiorenal syndrome. In the present study, we examined the effect of NG in rats with cardiorenal syndrome. We found

Acknowledgment

Author contributions: A.G. and Y.L. designed the experiments. Y.L. and W.A. did the experiments. A.G., Y.L., and W.A. wrote the article.

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