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Macelignan protects against renal ischemia-reperfusion injury via inhibition of inflammation and apoptosis of renal epithelial cells
Corresponding Author(s) : Jianjun Li
Cellular and Molecular Biology,
Vol. 66 No. 1: Issue 1
Abstract
Ischemia-reperfusion injury (IRI) refers to tissue damage that occurs when blood supply returns to tissue after a period of ischemia, anoxia or hypoxia. It occurs frequently during shock, organ transplantation and heart failure. It can cause impairment or even renal failure. Macelignan is a lignin isolated from the seeds of Myristica fragrans. It has been reported to inhibit neuroinflammation and oxidative toxicity. The preventive or therapeutic effects of macelignan on renal IRI has not been reported. The present study investigated the effects of macelignan on renal IRI in rats, and the underlying mechanism(s). Healthy adult male Sprague Dawley rats (n = 50) aged 7 – 9 weeks (mean weight = 220 ± 20 g) were used in this study. The rats were randomly assigned to five groups of 10 rats each: sham treated group, IRI group and 40 mg macelignan/kg body weight (bwt) group, 80 mg macelignan/kg bwt group, and 160 mg macelignan/kg bwt group. Ischemia-reperfusion injury was induced in the rats using standard procedure. The results showed that serum levels of creatinine, blood urea nitrogen (BUN), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and gamma interferon (IFN-γ) were significantly higher in IRI group than in sham treated group, but were significantly and dose-dependently reduced after treatment with macelignan (p < 0.05). The activities of catalase and superoxide dismutase (SOD), and reduced glutathione (GSH) level were significantly reduced in IRI group, when compared with sham treated group, but were significantly and dose-dependently increased after treatment with macelignan (p < 0.05). However, the level of malondialdehyde (MDA) was significantly higher in IRI group than in sham treated group, but treatment with macelignan reduced it significantly and dose-dependently (p < 0.05). Macelignan also significantly and dose-dependently inhibited IRI-induced apoptosis in epithelial cells of renal tubules (p < 0.05). The results of Western blotting showed that IRI significantly upregulated the expressions of bax and caspase-3, and down-regulated the expression of bcl-2 in epithelial cells of renal tubules (p < 0.05). However, treatment with macelignan significantly and dose-dependently down-regulated the expressions of bax and caspase-3 in these cells, but significantly and dose-dependently upregulated the expression of bcl-2. These results show that macelignan confers protection on renal IRI via mechanisms involving inhibition of inflammation and apoptosis, and stimulation of natural antioxidant defense system.
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- Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg 2001; 181: 160-166.
- Malek M, Nematbakhsh MJ. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev 2015; 4: 20.
- Barin-Le GC, Largeau B, Bon D, Marquet P, Hauet T. Ischemia/reperfusion-associated tubular cells injury in renal transplantation: Can metabolomics inform about mechanisms and help identify new therapeutic targets? J Pharmacol Res 2018; 129: 34-43.
- Lin M, Li L, Pokhrel G, Qi G, Rong R, Zhu T. The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis. BMC Complement Altern Med 2014; 14: 19.
- Cho K, Min SI, Ahn S, Min SK, Ahn C, Yu KS, et al. Integrative Analysis of Renal Ischemia/Reperfusion Injury and Remote Ischemic Preconditioning in Mice. J Proteome Res 2017; 16: 2877-2886.
- Westenfelder C, Togel FE. Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials. Kidney Inter Suppl 2011; 1: 103-106.
- Barrera-Chimal J, Bobadilla NA. Mineralocorticoid receptor antagonism: a promising therapeutic approach to treat ischemic AKI. Jaisser F Nephron 2016; 134: 10-13.
- Cai Y, Xu H, Yan J, Zhang L, Lu Y. Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep 2014; 9: 1542-1550.
- Olaleye M, Akinmoladun C, Akindahunsi A. Antioxidant properties of Myristica fragrans (Houtt) and its effect on selected organs of albino rats. Afr J Biotechnol 2006; 5: 1274-1278.
- Gupta AD, Bansal VK, Babu V, Maithil N. Chemistry, antioxidant and antimicrobial potential of nutmeg (Myristica fragrans Houtt). J Geod Biotechnol 2013; 11: 25-31.
- Choi EJ, Kang YG, Kim J, Hwang JK. Macelignan inhibits melanosome transfer mediated by protease-activated receptor-2 in keratinocytes. Biol Pharm Bull 2011; 34: 748-754.
- Sohn JH, Han KL, Choo JH, Hwang JK. Macelignan protects HepG2 cells against tert-butylhydroperoxide"induced oxidative damage. J Biofactors 2007; 29: 1-10.
- Jin DQ, Lim CS, Hwang JK, Ha I, Han JS. Anti-oxidant and anti-inflammatory activities of macelignan in murine hippocampal cell line and primary culture of rat microglial cells. Biochem Biophys Res Commun 2005; 331: 1264-1269.
- Shen S, Zhou J, Meng S, Wu J, Ma J, Zhu C, et al. The protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax. Exp Ther Med 2017; 14: 4077-4082.
- Sayhan MB, Kanter M, Oguz S, Erboga M. Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat. J Mol Histol 2012; 43: 691-698.
- Zheng Y, Lu M, Ma L, Zhang S, Qiu M, Wang Y. Osthole ameliorates renal ischemia-reperfusion injury in rats. Urol Int 2013; 91: 350-356.
- Chuan D, Zhang J, Rao J, Zhao C, Luan J. Application value of urinary calprotectin in differential diagnosis between prerenal and intrinsic pediatric acute renal injury. J Anaesthesiol Clin Pharmacol 2017; 32: 1097-1100.
- Nakamura K, Sano S, Fuster JJ, Kikuchi R, Shimizu I, Ohshima K, et al. Secreted frizzled-related protein 5 diminishes cardiac inflammation and protects the heart from ischemia/reperfusion injury. J Biol Chem 2016; 291: 2566-2575.
- Sun P, Liu J, Li W, Xu X, Gu X, Li H, et al. Human endometrial regenerative cells attenuate renal ischemia reperfusion injury in mice. J Transl Med 2016; 14: 28.
- Senthamizhselvan O, Manivannan J, Silambarasan T, Raja B. Diosmin pretreatment improves cardiac function and suppresses oxidative stress in rat heart after ischemia/reperfusion. Eur J Pharmacol 2014; 736: 131-137.
- Li H, Bian Y, Zhang N, Guo J, Wang C, Lau WB, et al. Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats. Cardiovasc Diabetol 2013; 12: 91.
- Kenan KM, Erkasap N, Kucuk A, Koken T, Tosun M. Effects of quercetin on apoptosis, NF-κB and NOS gene expression in renal ischemia/reperfusion injury. Exp Ther Med 2012; 3: 249-254.
- Havasi A, Borkan S. Apoptosis and acute kidney injury. Kidney Int 2011; 80: 29-40.
- Huang X, Brown C, Ni W, Maynard E, Rigby AC, Oettgen P. Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. Blood 2006; 107: 3153-3160.
References
Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg 2001; 181: 160-166.
Malek M, Nematbakhsh MJ. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev 2015; 4: 20.
Barin-Le GC, Largeau B, Bon D, Marquet P, Hauet T. Ischemia/reperfusion-associated tubular cells injury in renal transplantation: Can metabolomics inform about mechanisms and help identify new therapeutic targets? J Pharmacol Res 2018; 129: 34-43.
Lin M, Li L, Pokhrel G, Qi G, Rong R, Zhu T. The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis. BMC Complement Altern Med 2014; 14: 19.
Cho K, Min SI, Ahn S, Min SK, Ahn C, Yu KS, et al. Integrative Analysis of Renal Ischemia/Reperfusion Injury and Remote Ischemic Preconditioning in Mice. J Proteome Res 2017; 16: 2877-2886.
Westenfelder C, Togel FE. Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials. Kidney Inter Suppl 2011; 1: 103-106.
Barrera-Chimal J, Bobadilla NA. Mineralocorticoid receptor antagonism: a promising therapeutic approach to treat ischemic AKI. Jaisser F Nephron 2016; 134: 10-13.
Cai Y, Xu H, Yan J, Zhang L, Lu Y. Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep 2014; 9: 1542-1550.
Olaleye M, Akinmoladun C, Akindahunsi A. Antioxidant properties of Myristica fragrans (Houtt) and its effect on selected organs of albino rats. Afr J Biotechnol 2006; 5: 1274-1278.
Gupta AD, Bansal VK, Babu V, Maithil N. Chemistry, antioxidant and antimicrobial potential of nutmeg (Myristica fragrans Houtt). J Geod Biotechnol 2013; 11: 25-31.
Choi EJ, Kang YG, Kim J, Hwang JK. Macelignan inhibits melanosome transfer mediated by protease-activated receptor-2 in keratinocytes. Biol Pharm Bull 2011; 34: 748-754.
Sohn JH, Han KL, Choo JH, Hwang JK. Macelignan protects HepG2 cells against tert-butylhydroperoxide"induced oxidative damage. J Biofactors 2007; 29: 1-10.
Jin DQ, Lim CS, Hwang JK, Ha I, Han JS. Anti-oxidant and anti-inflammatory activities of macelignan in murine hippocampal cell line and primary culture of rat microglial cells. Biochem Biophys Res Commun 2005; 331: 1264-1269.
Shen S, Zhou J, Meng S, Wu J, Ma J, Zhu C, et al. The protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax. Exp Ther Med 2017; 14: 4077-4082.
Sayhan MB, Kanter M, Oguz S, Erboga M. Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat. J Mol Histol 2012; 43: 691-698.
Zheng Y, Lu M, Ma L, Zhang S, Qiu M, Wang Y. Osthole ameliorates renal ischemia-reperfusion injury in rats. Urol Int 2013; 91: 350-356.
Chuan D, Zhang J, Rao J, Zhao C, Luan J. Application value of urinary calprotectin in differential diagnosis between prerenal and intrinsic pediatric acute renal injury. J Anaesthesiol Clin Pharmacol 2017; 32: 1097-1100.
Nakamura K, Sano S, Fuster JJ, Kikuchi R, Shimizu I, Ohshima K, et al. Secreted frizzled-related protein 5 diminishes cardiac inflammation and protects the heart from ischemia/reperfusion injury. J Biol Chem 2016; 291: 2566-2575.
Sun P, Liu J, Li W, Xu X, Gu X, Li H, et al. Human endometrial regenerative cells attenuate renal ischemia reperfusion injury in mice. J Transl Med 2016; 14: 28.
Senthamizhselvan O, Manivannan J, Silambarasan T, Raja B. Diosmin pretreatment improves cardiac function and suppresses oxidative stress in rat heart after ischemia/reperfusion. Eur J Pharmacol 2014; 736: 131-137.
Li H, Bian Y, Zhang N, Guo J, Wang C, Lau WB, et al. Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats. Cardiovasc Diabetol 2013; 12: 91.
Kenan KM, Erkasap N, Kucuk A, Koken T, Tosun M. Effects of quercetin on apoptosis, NF-κB and NOS gene expression in renal ischemia/reperfusion injury. Exp Ther Med 2012; 3: 249-254.
Havasi A, Borkan S. Apoptosis and acute kidney injury. Kidney Int 2011; 80: 29-40.
Huang X, Brown C, Ni W, Maynard E, Rigby AC, Oettgen P. Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. Blood 2006; 107: 3153-3160.