Quercetin protects against oxidative stress-related renal dysfunction by cadmium in rats

Abstract

The aim of this study was to investigate the possible protective role of the dietary flavonoid quercetin on cadmium (Cd)-induced nephrotoxicity using biochemical and histopathological approaches. In experimental rats oral administration of CdCl₂ (5 mg/kg) for 4 weeks significantly induced renal damage which was evident from the increased levels of serum urea, uric acid and creatinine with a significant (p<0.05) decrease in creatinine clearance. Cd also significantly (p<0.05) decreased the levels of urea, uric acid and creatinine in urine. Cd-induced oxidative stress in kidney tissue was indicated by the increased levels of renal lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl content with a significant (p<0.05) decrease in non-enzymatic (total sulphydryl group, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose 6-phosphate dehydrogenase (G6PD)). Moreover the kidneys of Cd-treated rats showed tubular necrosis, degeneration, dilation, desquamation, thickening of basement membrane and luminal cast formation. Quercetin treatment markedly attenuated the Cd-induced biochemical alterations in serum, urine and renal tissue. Quercetin also ameliorated the Cd-induced pathological changes when compared with Cd-alone-treated group. These data indicate that the natural dietary antioxidant quercetin might have protective effect against Cd-induced nephrotoxicity and oxidative stress in rats.

Introduction

Cadmium is one of the most environmentally abundant toxic metals affecting numerous organs of the body. Cd, a widespread environmental pollutant remarkably notorious in its ability to cause kidney damage (Jarup et al., 1998), is found in air, drinking water, soil, plant and animal products. The flow of Cd in ecological systems increases through major sources such as mining, smelting and industrial use. Resources of human exposure to this metal include sea foods, cigarette smoke and beverages (Waalkes, 2000).

The molecular mechanisms of Cd toxicity are not yet well defined. In contrast with transition metals, the oxidative effect of Cd is indirect and based mainly on the depletion of sulphydryl (SH)-group-containing compounds (Rikans and Yamano, 2000). Cd itself is unable to generate free radicals directly; however indirect generation of various free radicals involving the superoxide radical and nitric oxide (NO) has been reported (Galan et al., 2001).

The pathobiochemical mechanism of Cd-induced renal damage is mainly via induction of oxidative free-radical stress (Manca, 1991). Cytosolic Cd indirectly generates reactive oxygen species (ROS) capable of depleting endogenous antioxidant status and inflicting peroxidative damage on biological membrane lipids and a variety of transport proteins, including Na⁺/K⁺ ATPase (Stohs and Bagchi, 1995). Cd has been reported to decrease renal ATPase activity, suggesting that the enzyme may be involved in the pathogenesis of Cd-induced nephropathy (Asagba et al., 2004). Several lines of evidences indicate that oxidative stress and reactive oxygen species formed in the presence of Cd could be responsible for its toxic effects in various organs (Watjen and Beyermann, 2004; Wang et al., 2004).

The nephrotoxic action of Cd may be mediated by Cd–metallothionein (MT) complex released from the damaged liver cells filtered through the glomerulus into the urinary space, where it is endocytosed by the proximal tubular cells and degraded by the lysosomes, resulting in the release of Cd (Morales et al., 2006a). The released Cd may then stimulate the production of MT in proximal tubular cells (Sendelbach and Klaassen, 1988), directly damage the integrity of microvilli and intracellular vesicles (Herak-Kramberger and Sabolic, 2001), indirectly inhibit the transporter activity through changes in the membrane fluidity due to oxidative stress, increase the lipid peroxidation by binding with membrane phospholipids (Shaikh et al., 1999) and target various intracellular proteins and membrane transporters at the cytoplasmic side by binding to their reactive SH groups (Vallee and Ulmer, 1972).

Efforts have been made to minimize the severity of Cd toxicity via enhanced sequestration and elimination using different agents. However in the case of chronic exposure, when Cd is bound to metallothionein, chelation therapy is ineffective (Nordberg, 1984). Antioxidant therapies have also been reported to exert protective effects on Cd toxicity (Morales et al., 2006a; Asagba et al., 2007; Renugadevi and Milton Prabu, 2009a). Considering the relationship between Cd exposure and oxidative stress, it is reasonable that administration of some antioxidant should be an important therapeutic approach in cadmium intoxication.

Quercetin is one of the most frequently studied bioflavonoid in the class of flavonols. Quercetin is present in high concentration in fruits and vegetables like apples, onion, mulberry, potatoes, broccoli, tea, peanuts, soybeans and red wine. It has been shown to have very potent antioxidant and cytoprotective effects in preventing endothelial apoptosis caused by oxidants (Choi et al., 2003). Treatment with quercetin has been shown to prevent liver damage and suppress overexpression of inducible form of nitric oxide synthase (iNOS), which is induced by various inflammatory stimuli (Pavanato et al., 2003). In addition quercetin is a more potent antioxidant than other antioxidant nutrients such as vitamin C, vitamin E and β-carotene on a molar basis (Rice-Evans et al., 1995) and can chelate transition metal ions, including iron, thus preventing iron-catalyzed Fenton reaction (Ferrali et al., 2000). Epidemiological studies have suggested that the intake of food containing flavonoids may be associated with reduced risk of coronary heart disease, hyper cholesterolemia, atherosclerosis and heart failure (Hollman and Katan, 1999; Stoclet et al., 2004).

In view of these considerations, the present study has been designed to elucidate whether the quercetin when administered with cadmium can ameliorate the oxidative stress-mediated renal dysfunction of Cd in terms of recovery in kidney oxidative stress markers, antioxidant status and histopathological pattern in rats.