Grape seed extract attenuates arsenic‑induced nephrotoxicity in rats

Zhang,Jiangong; Pan,Xinjuan; Li,Ning; Li,Xing; Wang,Yongchao; Liu,Xiaozhuan; Yin,Xinjuan; Yu,Zengli

doi:10.3892/etm.2013.1381

Grape seed extract attenuates arsenic‑induced nephrotoxicity in rats

Authors:
- Jiangong Zhang
- Xinjuan Pan
- Ning Li
- Xing Li
- Yongchao Wang
- Xiaozhuan Liu
- Xinjuan Yin
- Zengli Yu
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Affiliations: Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Published online on: November 5, 2013 https://doi.org/10.3892/etm.2013.1381
Pages: 260-266

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Abstract

Oxidative stress is a recognized factor in nephrotoxicity induced by chronic exposure to inorganic arsenic (As). Grape seed extract (GSE) possesses antioxidant properties. The present study was designed to evaluate the beneficial effects of GSE against arsenic‑induced renal injury. Healthy, male Sprague‑Dawley rats were exposed to As in drinking water (30 ppm) with or without GSE (100 mg/kg) for 12 months. The serum proinflammatory cytokine levels and mRNA expression levels of fibrogenic markers in the renal tissues were evaluated using enzyme‑linked immunosorbent assay and quantitative polymerase chain reaction, respectively. The protein expression levels of nicotinamide adenine dinucleotide phosphate (NADPH) subunits, transforming growth factor‑β1 (TGF‑β1) and phosphorylated Smad2/3 (pSmad2/3) were assessed using western blot analysis. The results demonstrated that cotreatment with GSE significantly improved renal function, as demonstrated by the reductions in relative kidney weight (% of body weight) and blood urea nitrogen, and the increase in the creatinine clearance capacity. GSE attenuated the As‑induced changes in the serum levels of tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6) and IL‑1β and the mRNA levels of TGF‑β1, α‑smooth muscle actin (α‑SMA), connective tissue growth factor (CTGF) and fibronectin (FN) in renal tissue. Furthermore, administration of GSE markedly reduced As‑stimulated reactive oxygen species (ROS) production and Nox activity, as well as the protein expression levels of the NADPH subunits (Nox2, p47phox and Nox4). In addition, GSE cotreatment was correlated with a significant reduction in TGF‑β/Smad signaling, as demonstrated by the decreased protein levels of TGF‑β1 and pSmad2/3 in renal tissue. This study indicated that GSE may be a useful agent for the prevention of nephrotoxicity induced by chronic exposure to As. GSE may exert its effects through the suppression of Nox and inhibition of TGF‑β/Smad signaling activation.

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1	Bao L and Shi H: Potential molecular mechanisms for combined toxicity of arsenic and alcohol. J Inorg Biochem. 104:1229–1233. 2010. View Article : Google Scholar : PubMed/NCBI
2	Eom SY, Lee YC, Yim DH, Lee CH, Kim YD, Choi BS, Park CH, Yu SD, Kim DS, Park JD and Kim H: Effects of low-level arsenic exposure on urinary N-acetyl-β-D-glucosaminidase activity. Hum Exp Toxicol. 30:1885–1891. 2011.
3	Chen JW, Chen HY, Li WF, Liou SH, Chen CJ, Wu JH and Wang SL: The association between total urinary arsenic concentration and renal dysfunction in a community-based population from central Taiwan. Chemosphere. 84:17–24. 2011. View Article : Google Scholar : PubMed/NCBI
4	Chen Y, Parvez F, Liu M, et al: Association between arsenic exposure from drinking water and proteinuria: results from the Health Effects of Arsenic Longitudinal Study. Int J Epidemiol. 40:828–835. 2011. View Article : Google Scholar : PubMed/NCBI
5	Kitchin KT: Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol. 172:249–261. 2001. View Article : Google Scholar
6	Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, Rhodes CJ and Valko M: Arsenic: toxicity, oxidative stress and human disease. J Appl Toxicol. 31:95–107. 2011.PubMed/NCBI
7	Kitchin KT and Ahmad S: Oxidative stress as a possible mode of action for arsenic carcinogenesis. Toxicol Lett. 137:3–13. 2003. View Article : Google Scholar : PubMed/NCBI
8	Kitchin KT and Conolly R: Arsenic-induced carcinogenesis - oxidative stress as a possible mode of action and future research needs for more biologically based risk assessment. Chem Res Toxicol. 23:327–335. 2010. View Article : Google Scholar : PubMed/NCBI
9	Brunati AM, Pagano MA, Bindoli A and Rigobello MP: Thiol redox systems and protein kinases in hepatic stellate cell regulatory processes. Free Radic Res. 44:363–378. 2010. View Article : Google Scholar : PubMed/NCBI
10	Samarakoon R, Overstreet JM, Higgins SP and Higgins PJ: TGF-β1→SMAD/p53/USF2→PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis. Cell Tissue Res. 347:117–128. 2012.
11	Liu Y: Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 69:213–217. 2006. View Article : Google Scholar : PubMed/NCBI
12	Liu Y: New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 21:212–222. 2010. View Article : Google Scholar : PubMed/NCBI
13	Derynck R and Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI
14	Iwano M and Neilson EG: Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens. 13:279–284. 2004. View Article : Google Scholar
15	Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA, Joshi SS and Pruess HG: Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology. 148:187–197. 2000. View Article : Google Scholar : PubMed/NCBI
16	Li WG, Zhang XY, Wu YJ and Tian X: Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds. Acta Pharmacol Sin. 22:1117–1120. 2001.PubMed/NCBI
17	Kris-Etherton PM, Lefevre M, Beecher GR, Gross MD, Keen CL and Etherton TD: Bioactive compounds in nutrition and health-research methodologies for establishing biological function: the antioxidant and anti-inflammatory effects of flavonoids on atherosclerosis. Annu Rev Nutr. 24:511–538. 2004. View Article : Google Scholar : PubMed/NCBI
18	Pan X, Dai Y, Li X, Niu N, Li W, Liu F, Zhao Y and Yu Z: Inhibition of arsenic induced-rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-β/Smad activation. Toxicol Appl Pharmacol. 254:323–331. 2011.PubMed/NCBI
19	Morris EM, Whaley-Connell AT, Thyfault JP, Britton SL, Koch LG, Wei Y, Ibdah JA and Sowers JR: Low aerobic capacity and high fat diet contributes to oxidative stress and IRS-1 degradation in the kidney. Am J Nephrol. 30:112–119. 2008. View Article : Google Scholar : PubMed/NCBI
20	Hu R, Wang YL, Edderkaoui M, Lugea A, Apte MV and Pandol SJ: Ethanol augments PDGF-induced NADPH oxidase activity and proliferation in rat pancreatic stellate cells. Pancreatology. 7:332–340. 2007. View Article : Google Scholar : PubMed/NCBI
21	Draper HH and Hadley M: Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 186:421–431. 1990. View Article : Google Scholar : PubMed/NCBI
22	Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S and Stadtman ER: Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 186:464–478. 1990. View Article : Google Scholar : PubMed/NCBI
23	Barnes JL and Gorin Y: Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 79:944–956. 2011. View Article : Google Scholar : PubMed/NCBI
24	Flora SJ, Chouhan S, Kannan GM, Mittal M and Swarnkar H: Combined administration of taurine and monoisoamyl DMSA protects arsenic induced oxidative injury in rats. Oxid Med Cell Longev. 1:39–45. 2008. View Article : Google Scholar : PubMed/NCBI
25	Dulundu E, Ozel Y, Topaloglu U, Toklu H, Ercan F, Gedik N and Sener G: Grape seed extract reduces oxidative stress and fibrosis in experimental biliary obstruction. J Gastroenterol Hepatol. 22:885–892. 2007. View Article : Google Scholar : PubMed/NCBI
26	Terra X, Montagut G, Bustos M, Llopiz N, Ardèvol A, Bladé C, Fernández-Larrea J, Pujadas G, Salvadó J, Arola L and Blay M: Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet. J Nutr Biochem. 20:210–218. 2009. View Article : Google Scholar : PubMed/NCBI
27	Mishra D and Flora SJ: Differential oxidative stress and DNA damage in rat brain regions and blood following chronic arsenic exposure. Toxicol Ind Health. 24:247–256. 2008. View Article : Google Scholar : PubMed/NCBI
28	Bhadauria S and Flora SJ: Response of arsenic-induced oxidative stress, DNA damage and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats. Cell Biol Toxicol. 23:91–104. 2007. View Article : Google Scholar : PubMed/NCBI
29	Nandi D, Patra RC and Swarup D: Oxidative stress indices and plasma biochemical parameters during oral exposure to arsenic in rats. Food Chem Toxicol. 44:1579–1584. 2006. View Article : Google Scholar : PubMed/NCBI
30	Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S and Cohen SM: Effects of co-administration of dietary sodium arsenite and an NADPH oxidase inhibitor on the rat bladder epithelium. Toxicology. 261:41–46. 2009. View Article : Google Scholar : PubMed/NCBI
31	Straub AC, Clark KA, Ross MA, Chandra AG, Li S, Gao X, Pagano PJ, Stolz DB and Barchowsky A: Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide. J Clin Invest. 118:3980–3989. 2008. View Article : Google Scholar : PubMed/NCBI
32	Okuda S, Languino LR, Ruoslahti E and Border WA: Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis: Possible role in expansion of the mesangial extracellular matrix. J Clin Invest. 86:453–462. 1990. View Article : Google Scholar
33	Gaedeke J, Peters H, Noble NA and Border WA: Angiotensin II, TGF-beta, and renal fibrosis. Contrib Nephrol. 135:153–160. 2001. View Article : Google Scholar : PubMed/NCBI
34	Bondi CD, Manickam N, Lee DY, Block K, Gorin Y, Abboud HE and Barnes JL: NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts. J Am Soc Nephrol. 21:93–102. 2010. View Article : Google Scholar : PubMed/NCBI
35	Okada H, Danoff TM, Kalluri R and Neilson EG: Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol. 273:F563–F574. 1997.PubMed/NCBI
36	Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC and Lan HY: Transforming growth factor beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int. 56:455–1467. 1999.PubMed/NCBI
37	Attisano L and Wrana JL: Signal transduction by the TGF-beta superfamily. Science. 296:1646–1647. 2002. View Article : Google Scholar : PubMed/NCBI
38	Schnaper HW, Hayashida T and Poncelet AC: It’s a Smad world: Regulation of TGF-beta signaling in the kidney. J Am Soc Nephrol. 13:1126–1128. 2002.