A new combination of naringin and trimetazidine protect kidney Mitochondria dysfunction induced by renal Ischemia / Reperfusion injury in rat

Authors

  • Negin Amini Departamento de Fisiologia, Escola de Medicina, Universidade de Ciências Médicas de Ahvaz Jundishapur, Ahvaz, Irã; Centro de Pesquisa em Fisiologia do Golfo Pérsico, Instituto de Pesquisa de Ciências Médicas Básicas, Escola de Medicina, Universidade de Ciências Médicas de Ahvaz Jundishapur, Ahvaz, Irã
  • Mohammad Badavi Departamento de Fisiologia, Escola de Medicina, Universidade de Ciências Médicas de Ahvaz Jundishapur, Ahvaz, Irã; Centro de Pesquisa em Fisiologia do Golfo Pérsico, Instituto de Pesquisa de Ciências Médicas Básicas, Escola de Medicina, Universidade de Ciências Médicas de Ahvaz Jundishapur, Ahvaz, Irã https://orcid.org/0000-0003-2290-8565
  • Mehdi Goudarzi Pesquisa de Plantas Medicinais Centro, Universidade de Ciências Médicas Ahvaz Jundishapur, Ahvaz, Irã

DOI:

https://doi.org/10.1590/s2175-97902022e19870

Keywords:

Mitochondria dysfunction, Naringin, Reactive oxygen species, I/R Injury, Trimetazidine

Abstract

Ischemia/reperfusion (IR) injury leads to overproduction of Reactive Oxygen Species (ROS), and disrupts membrane potential that contributes to cell death. The aim of this study was to determine if naringin (NAR), trimetazidine (TMZ) or their combination, protect the kidney mitochondrial from IR injury. Forty rats were randomly allocated into five groups, harboring eight rats each: Sham, IR, NAR (100 mg/kg), TMZ (5 mg/kg) and NAR plus TMZ. Ischemia was induced by obstructing both renal pedicles for 45 min, followed by reperfusion for 4 hours. The mitochondria were isolated to examine the ROS, Malondialdehyde (MDA), Glutathione (GSH), mitochondrial membrane potential (MMP) and mitochondrial viability (MTT). Our findings indicated that IR injury resulted in excessive ROS production, increased MDA levels and decreased GSH, MMP and MMT levels. However, NAR, TMZ or their combination reversed these changes. Interestingly, a higher protection was noted with the combination of both, compared to each drug alone. We speculate that this combination demonstrates a promising process for controlling renal failure, especially with the poor clinical outcome, acquired with NAR alone. This study revealed that pretreatment their combination serves as a promising compound against oxidative stress, leading to suppression of mitochondrial stress pathway and elevation of GSH level.

Downloads

Download data is not yet available.

References

Adil M, Kandhare AD, Ghosh P, Venkata S, Raygude KS, Bodhankar SL. Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: role of FXR and KIM-1. Ren Fail. 2016;38(6):1007-20.

Adil M, Kandhare AD, Visnagri A, Bodhankar SL. Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1, Caspase-3, TGF-beta, and TNF-alpha. Ren Fail . 2015;37(8):1396-407.

Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A, Badavi M. The renoprotective effects of naringin and trimetazidine on renal ischemia/reperfusion injury in rats through inhibition of apoptosis and down regulation of micoRNA-10a. Biomed Pharmacother. 2019a;112:108568. doi: 10.1016/j.biopha.2019.01.029.

» https://doi.org/10.1016/j.biopha.2019.01.029

Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A, Badavi M. Protective effects of naringin and trimetazidine on remote effect of acute renal injury on oxidative stress and myocardial injury through Nrf-2 regulation. Pharmacol Rep. 2019b;71(6):1059-1066.

Argaud L, Gomez L, Gateau-Roesch O, Couture-Lepetit E, Loufouat J, Robert D, et al. Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury. J Mol Cell Cardiol. 2005;39(6):893-9.

Baracca A, Sgarbi G, Solaini G, Lenaz G. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta. 2003;1606(1-3):137-46.

Baltaci AK, Gokbudak H, Baltaci SB, Mogulkoc R, Avunduk MC. The effects of resveratrol administration on lipid oxidation in experimental renal ischemia-reperfusion injury in rats. Biotech Histochem. 2019;94(8):592-599.

Bayram E, Atalay C, Kocaturk H, Yucel O. Effects of trimetazidine on lipid peroxidation, antioxidant enzyme activities and plasma brain natriuretic peptide levels in patients with chronic corpulmonale. J Int Med Res. 2005;33(6):612-9.

Bonventre JV. Mechanisms of ischemic acute renal failure. Kidney Int.1993;43(5):1160-78.

Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest. 2011;121(11):4210-21.

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem.1976;72(1):248-54.

Cau J, Favreau F, Tillement JP, Lerman LO, Hauet T, Goujon JM. Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: a dose effect study. J Vasc Surg. 2008;47(4):852-60.

Chatterjee PK, Brown PA, Cuzzocrea S, Zacharowski K, Stewart KN, Mota-Filipe H, et al. Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney Int . 2001;59(6):2073-83.

Chen JJ, Yu BP. Alterations in mitochondrial membrane fluidity by lipid peroxidation products. Free Radic Biol Med.1994;17(5):411-8.

Chen R, Qi QL, Wang MT, Li QY. Therapeutic potential of naringin: an overview. Pharm Biol. 2016;54(12):3203-3210.

Choe SC, Kim HS, Jeong TS, Bok SH, Park YB. Naringin has an antiatherogenic effect with the inhibition of intercellular adhesion molecule-1 in hypercholesterolemic rabbits. J Cardiovasc Pharmacol. 2001;38(6):947-55.

Elimadi A, Settaf A, Morin D, Sapena R, Lamchouri F, Cherrah Y. Trimetazidine counteracts the hepatic injury associated with ischemia-reperfusion by preserving mitochondrial function. J Pharmacol Exp Ther. 1998;286(1):23-28.

Gaur V, Aggarwal A, Kumar A. Protective effect of naringin against ischemic reperfusion cerebral injury: possible neurobehavioral, biochemical and cellular alterations in rat brain. Eur J Pharmacol. 2009;616(1-3):147-54.

Grekas D, Dioudis C, Papageorgiou G, Iliadis S, Zilidis C, Alivanis P, et al. Lipid peroxidation after acute renal ischemia and reperfusion in rats: the effect of trimetazidine. Ren Fail .1996;18(4):545-52.

Groeneveld AB, Tran DD, van der Meulen J, Nauta JJ, Thijs LG. Acute renal failure in the medical intensive care unit: predisposing, complicating factors and outcome. Nephron. 1991;59(4):602-10.

Hosseini F, Naseri MK, Badavi M, Ghaffari MA, Shahbazian H, Rashidi I, et al. Effect of beta carotene on lipid peroxidation and antioxidant status following renal ischemia/reperfusion injury in rat. Scand J Clin Lab Invest. 2010;70(4):259-63.

Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J. Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ROS production. Cell Biochem Biophys. 2014;70(1):367-81.

Hussein AA, El-Dken ZH, Barakat N, Abol-Enein H. Renal ischaemia/reperfusion injury: possible role of aquaporins. Acta Physiol. 2012;204(3):308-16.

Jassem W, Fuggle SV, Rela M, Koo DD, Heaton ND. The role of mitochondria in ischemia/reperfusion injury. Transplantation. 2002;73(4):493-9.

Jassem W, Heaton ND. The role of mitochondria in ischemia/ reperfusion injury in organ transplantation. Kidney Int . 2004;66(2):514-17.

Kovacs A, Moricz K, Albert M, Benedek A, Harsing LG, Szenasi G. Decreased vasoconstrictor responses in remote cerebral arteries after focal brain ischemia and reperfusion in the rat, in vitro. Eur J Pharmacol . 2010;644(1-3):154-9.

Lash LH, Putt DA, Matherly LH. Protection of NRK-52E cells, a rat renal proximal tubular cell line, from chemical-induced apoptosis by overexpression of a mitochondrial glutathione transporter. J Pharmacol Exp Ther . 2002;03(2):476-86.

Lee JI, Son HY, Kim MC. Attenuation of ischemia- reperfusion injury by ascorbic acid in the canine renal transplantation. J Vet Sci. 2006;7(4):375-9.

Lieberthal W, Levine JS. Mechanisms of apoptosis and its potential role in renal tubular epithelial cell injury. Am J Physiol. 1996;271(3 Pt 2):F477-88.

Maleki M, Nematbakhsh M. Renal blood flow response to angiotensin 1-7 versus hypertonic sodium chloride 7.5% administration after acute hemorrhagic shock in rats. Int J Vasc Med. 2016;2016:6562017.

Mari M, Morales A, Colell A, Garcia-Ruiz C, Fernandez- Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11(11):2685-700.

Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1-2):55-63.

Nadkarni GN, Konstantinidis I, Patel A, Yacoub R, Kumbala D, Patel RA, et al. Trimetazidine decreases risk of contrast- induced nephropathy in patients with chronic kidney disease: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol Ther. 2015;20(6):539-46.

Najafi H, Changizi Ashtiyani S, Sayedzadeh SA, Mohamadi Yarijani Z, Fakhri S. Therapeutic effects of curcumin on the functional disturbances and oxidative stress induced by renal ischemia/reperfusion in rats. Avicenna J Phytomed. 2015;5(6):576-86.

Nesic Z, Todorovic Z, Stojanovic R, Basta-Jovanovic G, Radojevic-Skodric S, Velickovic R, et al. Single-dose intravenous simvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in the rat. J Pharmacol Sci. 2006;102(4):413-17.

Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol. 2007;83(1):84-92.

Rajadurai M, Prince PS. preventive effect of naringin on cardiac mitochondrial enzymes during isoproterenol- induced myocardial infarction in rats: a transmission electron microscopic study. J Biochem Mol Toxicol. 2007;21(6):354-61.

Ranjbar A, Kheiripour N, Ghasemi H, Seif Rabiei MA, Dadras F, Khoshjou F. Antioxidative effects of tempol on mitochondrial dysfunction in diabetic nephropathy. Iran J Kidney Dis. 2018;12(2):84-90.

Rao VK, Carlson EA, Yan SS. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta . 2014;1842(8):1267-72.

Ribas V, García-Ruiz C, Fernández-Checa JC. Glutathione and mitochondria. Front Pharmacol. 2014;5:151.

Sachdeva AK, Kuhad A, Chopra K. Naringin ameliorates memory deficits in experimental paradigm of Alzheimer’s disease by attenuating mitochondrial dysfunction. Pharmacol Biochem Behav. 2014;127:101-10.

Sadegh C, Schreck RP. The spectroscopic determination of aqueous sulfite using Ellman’s reagent. MURJ. 2003;8:39-43.

Serviddio G, Romano AD, Gesualdo L, Tamborra R, Di Palma AM, Rollo T, et al. Post conditioning is an effective strategy to reduce renal ischaemia/reperfusion injury. Nephrol Dial Transplant. 2008;23(5):1504-12.

Singh D, Chander V, Chopra K. Protective effect of naringin, a bioflavonoid on glycerol-induced acute renal failure in rat kidney. Toxicology. 2004;201(1-3):143-51.

Singh D, Chopra K. The effect of naringin, a bioflavonoid on ischemia-reperfusion induced renal injury in rats. Pharmacol Res. 2004;50(2):187-93.

Spargias K, Alexopoulos E, Kyrzopoulos S, Iokovis P, Greenwood DC, Manginas A, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004;110(18):2837-42.

Sulikowski T, Domanski L, Ciechanowski K, Adler G, Pawlik A, Safranow K, et al. Effect of trimetazidine on xanthine oxidoreductase expression in rat kidney with ischemia-- reperfusion injury. Arch Med Res. 2008;39(4):459-62.

Sureshbabu A, Ryter SW, Choi ME. Oxidative stress and autophagy: Crucial modulators of kidney injury. Redox Biol. 2015;4:208-14.

Suzer T, Coskun E, Demir S, Tahta K. Lipid peroxidation and glutathione levels after cortical injection of ferric chloride in rats: effect of trimetazidine and deferoxamine. Res Exp Med. 2000;199(4):223-9.

Visnagri A, Kandhare AD, Bodhankar SL. Renoprotective effect of berberine via intonation on apoptosis and mitochondrial-dependent pathway in renal ischemia reperfusion-induced mutilation. Ren Fail . 2015;37(3):482-93.

Wilcox LJ, Borradaile NM, Huff MW. Antiatherogenic properties of naringenin, a citrus flavonoid. Cardiovasc Drug Rev. 1999;17(2):160-78.

Yu W, Sheng M, Xu R, Yu J, Cui K, Tong J, et al. Berberine protects human renal proximal tubular cells from hypoxia/ reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. J Transl Med. 2013;11:24. doi:10.1186/1479-5876-11-24

» https://doi.org/10.1186/1479-5876-11-24

Zhang F, Xu Z, Gao J, Xu B, Deng Y. In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. Environ Toxicol Pharmacol. 2008;26(2):232-6.

Downloads

Published

2022-11-23

Issue

Section

Original Article

How to Cite

A new combination of naringin and trimetazidine protect kidney Mitochondria dysfunction induced by renal Ischemia / Reperfusion injury in rat. (2022). Brazilian Journal of Pharmaceutical Sciences, 58. https://doi.org/10.1590/s2175-97902022e19870

Funding data