The role of S-methylisothiourea hemisulfate as inducible nitric oxide synthase inhibitor against kidney iron deposition in iron overload rats

Authors

1 Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran

3 Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan; Department of Physiology, Isfahan University of Medical Sciences, Isfahan; Isfahan MN Institute of Basic and Applied Sciences Research, Isfahan, Iran

Abstract

Background: Iron dextran is in common use to maintain iron stores. However, it is potentially toxic and may lead to iron deposition (ID) and impair functions of organs. Iron overload can regulate the expression of inducible nitric oxide synthase (iNOS) in some cells that has an important role in tissue destruction. S-methylisothiourea hemisulfate (SMT) is a direct inhibitor of iNOS, and this study was designed to investigate the effect of SMT against kidney ID in iron overload rats.
Materials and Methods: 24 Wistar rats (male and female) were randomly assigned to two groups. Iron overloading was performed by iron dextran 100 mg/kg/day every other day for 2 weeks. In addition, during the study, groups 1 and 2 received vehicle and SMT (10 mg/kg, ip), respectively. Finally, blood samples were obtained, and the kidneys were prepared for histopathological procedures.




Results: SMT significantly reduced the serum levels of creatinine and blood urea nitrogen. However, SMT did not alter the serum levels of iron and nitrite, and the kidney tissue level of nitrite. Co-administration of SMT with iron dextran did not attenuate the ID in the kidney.




Conclusion: SMT, as a specific iNOS inhibitor, could not protect the kidney from ID while it attenuated the serum levels of kidney function biomarkers.

Keywords

1.
Hou Y, Zhang S, Wang L, Li J, Qu G, He J, et al. Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Gene 2012;511:398-403.  Back to cited text no. 1
    
2.
Zhang Y, Zhang Y, Xie Y, Gao Y, Ma J, Yuan J, et al. Multitargeted inhibition of hepatic fibrosis in chronic iron-overloaded mice by Salvia miltiorrhiza. J Ethnopharmacol 2013;148:671-81.  Back to cited text no. 2
    
3.
Adams RL, Bird RJ. Safety and efficacy of deferasirox in the management of transfusion-dependent patients with myelodysplastic syndrome and aplastic anaemia: a perspective review. Ther Adv Hematol 2013;4:93-102.  Back to cited text no. 3
    
4.
Lu N, Li X, Li J, Xu W, Li H, Gao Z. Nitrative and oxidative modifications of enolase are associated with iron in iron-overload rats and in vitro. J Biol Inorg Chem 2011;16:481-90.  Back to cited text no. 4
    
5.
Koliakos G, Papachristou F, Koussi A, Perifanis V, Tsatra I, Souliou E, et al. Urine biochemical markers of early renal dysfunction are associated with iron overload in beta-thalassaemia. Clin Lab Haematol 2003;25:105-9.  Back to cited text no. 5
    
6.
Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J. Body iron metabolism and pathophysiology of iron overload. Int J Hematol 2008;88:7-15.  Back to cited text no. 6
    
7.
Vaziri ND. Understanding iron: Promoting its safe use in patients with chronic kidney failure treated by hemodialysis. Am J Kidney Dis 2013;61:992-1000.  Back to cited text no. 7
    
8.
Rusovici A, Ibrahim S, Sood S, Maher J, Gerula C, Kaluski E, et al. Extensive myocardial iron deposition in a patient with hepatitis C. Tex Heart Inst J 2012;39:281-3.  Back to cited text no. 8
    
9.
Schneider SA, Bhatia KP. Excess iron harms the brain: The syndromes of neurodegeneration with brain iron accumulation (NBIA). J Neural Transm 2013;120:695-703.  Back to cited text no. 9
    
10.
Nematbakhsh M, Pezeshki Z, Moaeidi BA, Eshraghi-Jazi F, Talebi A, Nasri H, et al. Protective role of silymarin and deferoxamine against iron dextran-induced renal iron deposition in male rats. Int J Prev Med 2013;4:286-92.  Back to cited text no. 10
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11.
Cornejo P, Varela P, Videla LA, Fernández V. Chronic iron overload enhances inducible nitric oxide synthase expression in rat liver. Nitric Oxide 2005;13:54-61.  Back to cited text no. 11
    
12.
Almeida RM, Sousa JB, Ribeiro PR, Silva SM, Firmino MA, Oliveira PG. Evaluation of the effects of S-methylisothiourea hemisulfate, an inducible nitric oxide synthase inhibitor, on the healing of colonic anastomosis in rats. Acta Cir Bras 2012;27:892-6.  Back to cited text no. 12
    
13.
Pechenik JA, Cochrane DE, Li W, West ET, Pires A, Leppo M. Nitric oxide inhibits metamorphosis in larvae of Crepidula fornicata, the slippershell snail. Biol Bull 2007;213:160-71.  Back to cited text no. 13
    
14.
Lucesoli F, Fraga CG. Oxidative stress in testes of rats subjected to chronic iron intoxication and alpha-tocopherol supplementation. Toxicology 1999;132:179-86.  Back to cited text no. 14
    
15.
Szabó C, Southan GJ, Thiemermann C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci U S A 1994;91:12472-6.  Back to cited text no. 15
    
16.
Wen S, Huang TH, Li GQ, Yamahara J, Roufogalis BD, Li Y. Bromelain improves decrease in defecation in postoperative rats: Modulation of colonic gene expression of inducible nitric oxide synthase. Life Sci 2006;78:995-1002.  Back to cited text no. 16
    
17.
Takimoto Y, Aoyama T, Keyamura R, Shinoda E, Hattori R, Yui Y, et al. Differential expression of three types of nitric oxide synthase in both infarcted and non-infarcted left ventricles after myocardial infarction in the rat. Int J Cardiol 2000;76:135-45.  Back to cited text no. 17
    
18.
Chen LW, Hsu CM, Wang JS, Chen JS, Chen SC. Specific inhibition of iNOS decreases the intestinal mucosal peroxynitrite level and improves the barrier function after thermal injury. Burns 1998;24:699-705.  Back to cited text no. 18
    
19.
Ohsugi S, Iwasaki Y, Takemura Y, Nagata K, Harada H, Yokomura I, et al. An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury. Biomed Res 2007;28:91-9.  Back to cited text no. 19
    
20.
Nakanishi H, Zhang J, Koike M, Nishioku T, Okamoto Y, Kominami E, et al. Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice. J Neurosci 2001;21:7526-33.  Back to cited text no. 20
    
21.
Pimková K, Chrastinová L, Suttnar J, Štikarová J, Kotlín R, Cermák J, et al. Plasma levels of aminothiols, nitrite, nitrate, and malondialdehyde in myelodysplastic syndromes in the context of clinical outcomes and as a consequence of iron overload. Oxid Med Cell Longev 2014;2014:416028.  Back to cited text no. 21
    
22.
Tsai SK, Hung LM, Fu YT, Cheng H, Nien MW, Liu HY, et al. Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats. J Vasc Surg 2007;46:346-53.  Back to cited text no. 22
    
23.
Shiva S. Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function. Redox Biol 2013;1:40-44.  Back to cited text no. 23
    
24.
Li H, Forstermann U. Pharmacological prevention of eNOS uncoupling. Curr Pharm Des 2014;20:3595-606.  Back to cited text no. 24
    
25.
Zhou XJ, Laszik Z, Wang XQ, Silva FG, Vaziri ND. Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis. Lab Invest 2000;80:1905-14.  Back to cited text no. 25
    
26.
Wildhirt SM, Suzuki H, Horstman D, Weismüller S, Dudek RR, Akiyama K, et al. Selective modulation of inducible nitric oxide synthase isozyme in myocardial infarction. Circulation 1997;96:1616-23.  Back to cited text no. 26
    
27.
Zhao T, Xi L, Chelliah J, Levasseur JE, Kukreja RC. Inducible nitric oxide synthase mediates delayed myocardial protection induced by activation of adenosine A (1) receptors: evidence from gene-knockout mice. Circulation 2000;102:902-7.  Back to cited text no. 27
    
28.
Kelm M, Preik-Steinhoff H, Preik M, Strauer BE. Serum nitrite sensitively reflects endothelial NO formation in human forearm vasculature: Evidence for biochemical assessment of the endothelial L-arginine-NO pathway. Cardiovasc Res 1999;41:765-72.  Back to cited text no. 28
    
29.
Hetzel J, Balletshofer B, Rittig K, Walcher D, Kratzer W, Hombach V, et al. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers. Arterioscler Thromb Vasc Biol 2005;25:1804-9.  Back to cited text no. 29
    
30.
Metzger IF, Sertorio JT, Tanus-Santos JE. Relationship between systemic nitric oxide metabolites and cyclic GMP in healthy male volunteers. Acta Physiol (Oxf) 2006;188:123-7.  Back to cited text no. 30
    
31.
Lucesoli F, Fraga CG. Oxidative damage to lipids and DNA concurrent with decrease of antioxidants in rat testes after acute iron intoxication. Arch Biochem Biophys 1995;316:567-71.  Back to cited text no. 31
    
32.
O'Bryan MK, Schlatt S, Gerdprasert O, Phillips DJ, de Kretser DM, Hedger MP. Inducible nitric oxide synthase in the rat testis: Evidence for potential roles in both normal function and inflammation-mediated infertility. Biol Reprod 2000;63:1285-93.  Back to cited text no. 32
    
33.
Kolasa A, Marchlewicz M, Kurzawa R, Glabowski W, Trybek G, Wenda-Rózewicka L, et al. The expression of inducible nitric oxide synthase (iNOS) in the testis and epididymis of rats with a dihydrotestosterone (DHT) deficiency. Cell Mol Biol Lett 2009;14:511-27.  Back to cited text no. 33
    
34.
Kudo H, Suzuki S, Watanabe A, Kikuchi H, Sassa S, Sakamoto S. Effects of colloidal iron overload on renal and hepatic siderosis and the femur in male rats. Toxicology 2008;246:143-7.  Back to cited text no. 34
    
35.
Gupta A, Sharma S, Chopra K. Reversal of iron-induced nephrotoxicity in rats by molsidomine, a nitric oxide donor. Food Chem Toxicol 2008;46:537-43.  Back to cited text no. 35
    
36.
Prabhakar SS, Zeballos GA, Montoya-Zavala M, Leonard C. Urea inhibits inducible nitric oxide synthase in macrophage cell line. Am J Physiol 1997;273:C1882-8.  Back to cited text no. 36
    
37.
Mitchell LM, Kennedy CR, Hartshorne GM. Pharmacological manipulation of nitric oxide levels in mouse follicle cultures demonstrates key role of extrafollicular control of ovulation. Hum Reprod 2004;19:1705-12.  Back to cited text no. 37