Nephroprotective action of tocotrienol-rich fraction (TRF) from palm oil against potassium dichromate (K2Cr2O7)-induced acute renal injury in rats
Introduction
Hexavalent chromium Cr(VI) is stable in the ambient environment and known to cause toxicity in humans and animals [1]. It is a strong oxidizing agent, causes dermatotoxicity, immunotoxicity, neurotoxicity, genotoxicity, cytotoxicity, mutagenesis and carcinogenicity [2]. The main site of Cr induced nephropathy in rats [3] and humans [4] is the proximal tubule, although other segments of the nephron might also be affected. Cr(VI) can easily enter many types of cells through SO42− and HPO42− channels [5]. The intracellular reduction of chromium(VI) via H2O2 produces reactive oxygen species (ROS). The most important mechanisms of oxygen activation by Cr(VI) involve Fenton-like reaction to generate the powerful DNA-damaging hydroxyl radical (HO) [2]. C(VI) causes nitrosative stress by reducing nitric oxide (NO) bioavailability [6], [7] and lipid peroxidation through the overproduction of (ROS) [8]. The role of oxidative stress in the renal damage induced by K2Cr2O7 has been supported by the fact that some antioxidants ameliorate K2Cr2O7-induced nephrotoxicity and oxidative damage [9], [10], [11], [12], whereas the inhibition of glutathione biosynthesis enhances it [13].
We have shown in our previous study, that Pycnogenol pre-treatment has a protective role in K2Cr2O7-induced nephrotoxicity [14]. Therefore, antioxidants have been considered for prevention of nephropathy progression by reducing oxidative stress and/or preserving NO bioavailability. It has been shown that vitamin E is a naturally occurring, potent lipid-soluble, chain-breaking antioxidant that scavenges ROS and lipid peroxyl radicals both in vitro and in vivo[9], [15]. It protects the integrity of membrane by inhibiting lipid peroxidation and augmenting the activity of antioxidant enzymes in the kidneys of diabetic rats [16] and is also shown to suppress oxidative stress and glomerulosclerosis in rat remnant kidney [17] along with protecting against cisplatin-induced nephrotoxicity in developing rats [18]. Vitamin E is the generic term for a group of four tocopherols (TOC) and four tocotrienols (T3) (Fig. 1). T3 qualitatively exhibit the biological activity of α-tocopherol. TOC and T3 share structural features, namely a common chromanol head and a side chain at the C-2 position. The difference between TOC and T3 is that the former have a saturated phytyl tail, whereas the later possess an unsaturated isoprenoid (farnesyl) side chain. TOC and T3 are further separated into eight individual compounds (α-, β-, γ-, δ-TOC or T3) differing in the number and position of methyl substitutions on the chromanol ring. T3 have been poorly studied as compared to TOC [19]. Several investigators reported that T3 have greater antioxidant activity than TOC and protect more efficiently against some free radical-related diseases than does TOC [20], [21], [22], [23], [24]. At nanomolar concentration, α-T3, not α-TOC, prevents stroke-related neurodegeneration [24].
Palm oil contains more than 70% T3, which consists of α-, β-, γ-, δ-tocotrienols [25]. Although, the pharmacotherapeutic properties of tocotrienol-rich fraction (TRF) from palm oil are well known, the nephroprotective role of TRF has not previously been investigated. The aim of this study was to examine the protective effect of TRF against acute renal injury (ARI) caused by the acute exposure to potassium dichromate. The study also analysed the alterations in the function of the different segments (glomeruli and proximal tubules) of the nephron.
Section snippets
Chemicals and reagents
Glutathione (GSH), 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB), thiobarbituric acid (TBA), and 2,4-dinitrophenylhydrazine (DNPH), sulphanilamide (SULF), N-(1-naphthyl) ethylenediamine dihydrochloride (NED), vanadium(III) chloride (VCl3), sodium nitrite, sodium nitrate, p-nitrophenyl-N-acetyl-β-d-glucosaminide, sulfamic acid and potassium dichromate (K2Cr2O7) were purchased from Sigma–Aldrich Chemicals Pvt. Ltd., India. TRF from palm oil was purified in our lab by standardized method mentioned
Statistical analysis
Results are expressed as mean ± standard deviation (S.D.). The statistical significance of differences between the experimental groups was calculated by ANOVA followed by Tukey–Kramer tests. Analyses were performed using the statistical software Graph Pad InStat v 3 (San Diego, CA). Results were considered significant at P < 0.001.
TRF supplementation reduces proximal tubular dysfunction elicited by dichromate administration
Proximal tubules perform the reabsorptive function of organic molecules, especially glucose. Fractional excretion of glucose (FEGlc) was therefore measured to assess tubular function, as it is an adequate indicator of glucose reabsorption and transport. The urinary loss of glucose significantly increased due to tubular cell damage after dichromate administration, steadily from day 1 to day 10 and then returned to control values (Fig. 2(A)). Persistently elevated urinary excretion of glucose
Discussion
In the present study, we have demonstrated the nephroprotective effects of tocotrienol-rich fraction (TRF) obtained from palm oil, against potassium dichromate induced acute renal injury (ARI). It was shown that TRF exhibited a potent nephroprotective effect at 200 mg/kg bw once daily owing to its antioxidative properties. Our results are consistent with the previous findings that the dichromate causes nephrotoxicity to the different segments of the nephron, which leads to acute tubular necrosis
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgements
The financial support from Indian council of medical research, Government of India in the form of senior research fellowship (SRF), is acknowledged. We thank Dr. Zeenat Iqbal, Department of pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India for providing TRF characterization service.
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