Role of endothelin-1 antagonist; bosentan, against cisplatin-induced nephrotoxicity in male and female rats

Authors

1 Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan; Department of Physiology, Islamic Azad University, Jahrom Brunch, Jahrom, Iran

2 Department of Physiology, Islamic Azad University, Jahrom Brunch, Jahrom; Department of Physiology, Isfahan University of Medical Sciences; Isfahan MN Institute of Basic and Applied Sciences Research, Isfahan, Iran

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

Abstract

Background: Cisplatin (CP) is a chemotherapy drug, with the major side effect of nephrotoxicity. The level of endothelin-1 (ET-1) increases during nephrotoxicity, which is accompanied with vasoconstrictive properties. Bosentan (BOS) is a nonselective ET-1 receptor antagonist, having vasodilatory and anti-hypertension effects. The purpose of this study was to investigate the renoprotective effect of BOS against CP-induced nephrotoxicity in male and female rats.
Materials and Methods: Male and female rats were divided into six groups; groups 1-3 and 4-6 were male and female rats, respectively. Animals in groups 1 and 4 were considered as negative control and groups 2 and 5 considered as positive control groups received BOS (30 mg/kg/day) alone and CP (2.5 mg/kg/day) alone, respectively, for 1-week. The animals in groups 3 and 6 were treated with both CP and BOS. Finally, serum parameters were measured, and the kidney tissue was subjected to staining to evaluate tissue damage.
Results: The serum levels of blood urea nitrogen and creatinine, kidney tissue damage score and kidney weight elevated, and body weight significantly decreased in both CP alone and in CP plus BOS-treated groups when compared with the control groups (P < 0.05), while BOS did not ameliorate these parameters neither in males nor in females. No significant differences were observed in serum levels of nitrite and malondialdehyde between the groups, but kidney tissue level of nitrite decreased significantly in CP alone and CP plus BOS-treated groups (P < 0.05).
Conclusion: Renoprotective effect of BOS, as ET-1 blocker, was not observed against CP-induced nephrotoxicity neither in male nor in female rats. This is while BOS promoted the severity of injuries in females.

Keywords

1.
Hartmann JT, Fels LM, Knop S, Stolt H, Kanz L, Bokemeyer C. A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs 2000;18:281-9.  Back to cited text no. 1
    
2.
Hartmann JT, Knop S, Fels LM, van Vangerow A, Stolte H, Kanz L, et al. The use of reduced doses of amifostine to ameliorate nephrotoxicity of cisplatin/ifosfamide-based chemotherapy in patients with solid tumors. Anticancer Drugs 2000;11:1-6.  Back to cited text no. 2
    
3.
Blakley BW, Gupta AK, Myers SF, Schwan S. Risk factors for ototoxicity due to cisplatin. Arch Otolaryngol Head Neck Surg 1994;120:541-6.  Back to cited text no. 3
    
4.
Liu J, Liu Y, Habeebu SS, Klaassen CD. Metallothionein (MT)-null mice are sensitive to cisplatin-induced hepatotoxicity. Toxicol Appl Pharmacol 1998;149:24-31.  Back to cited text no. 4
    
5.
Nematbakhsh M, Ashrafi F, Pezeshki Z, Fatahi Z, Kianpoor F, Sanei MH, et al. A histopathological study of nephrotoxicity, hepatoxicity or testicular toxicity: Which one is the first observation as side effect of Cisplatin-induced toxicity in animal model? J Nephropathol 2012;1:190-3.  Back to cited text no. 5
    
6.
Safirstein R, Miller P, Guttenplan JB. Uptake and metabolism of cisplatin by rat kidney. Kidney Int 1984;25:753-8.  Back to cited text no. 6
    
7.
Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002;110:835-42.  Back to cited text no. 7
    
8.
Santos NA, Catão CS, Martins NM, Curti C, Bianchi ML, Santos AC. Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol 2007;81:495-504.  Back to cited text no. 8
    
9.
Soltani N, Nematbakhsh M, Eshraghi-Jazi F, Talebi A, Ashrafi F. Effect of oral administration of magnesium on Cisplatin-induced nephrotoxicity in normal and streptozocin-induced diabetic rats. Nephrourol Mon 2013;5:884-90.  Back to cited text no. 9
    
10.
Ashrafi F, Haghshenas S, Nematbakhsh M, Nasri H, Talebi A, Eshraghi-Jazi F, et al. The role of magnesium supplementation in cisplatin-induced nephrotoxicity in a rat model: No nephroprotectant effect. Int J Prev Med 2012;3:637-43.  Back to cited text no. 10
[PUBMED]  Medknow Journal  
11.
Lee S, Ahn D. Expression of endothelin-1 and its receptors in Cisplatin-induced acute renal failure in mice. Korean J Physiol Pharmacol 2008;12:149-53.  Back to cited text no. 11
    
12.
Winston JA, Safirstein R. Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat. Am J Physiol 1985;249:F490-6.  Back to cited text no. 12
    
13.
Bagnato A, Spinella F, Rosanò L. Emerging role of the endothelin axis in ovarian tumor progression. Endocr Relat Cancer 2005;12:761-72.  Back to cited text no. 13
    
14.
Ohlstein EH, Elliott JD, Feuerstein GZ, Ruffolo RR Jr. Endothelin receptors: Receptor classification, novel receptor antagonists, and potential therapeutic targets. Med Res Rev 1996;16:365-90.  Back to cited text no. 14
    
15.
Agapitov AV, Haynes WG. Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 2002;3:1-15.  Back to cited text no. 15
    
16.
Takaoka M, Kuro T, Matsumura Y. Role of endothelin in the pathogenesis of acute renal failure. Drug News Perspect 2000;13:141-6.  Back to cited text no. 16
    
17.
Hoffman A, Grossman E, Goldstein DS, Gill JR Jr, Keiser HR. Urinary excretion rate of endothelin-1 in patients with essential hypertension and salt sensitivity. Kidney Int 1994;45:556-60.  Back to cited text no. 17
    
18.
Roux S, Breu V, Ertel SI, Clozel M. Endothelin antagonism with bosentan: A review of potential applications. J Mol Med (Berl) 1999;77:364-76.  Back to cited text no. 18
    
19.
Safari T, Nematbakhsh M, Hilliard LM, Evans RG, Denton KM. Sex differences in the renal vascular response to angiotensin II involves the Mas receptor. Acta Physiol (Oxf) 2012;206:150-6.  Back to cited text no. 19
    
20.
Safari T, Nematbakhsh M. Angiotensin 1-7 receptor and angiotensin II receptor 2 blockades prevent the increased serum and kidney nitric oxide levels in response to angiotensin II administration: Gender-related difference. Int J Prev Med 2013;4:311-5.  Back to cited text no. 20
[PUBMED]  Medknow Journal  
21.
Ergul A, Shoemaker K, Puett D, Tackett RL. Gender differences in the expression of endothelin receptors in human saphenous veins in vitro. J Pharmacol Exp Ther 1998;285:511-7.  Back to cited text no. 21
    
22.
Sweileh WM. Gender differences in aminoglycoside induced nephrotoxicity: A prospective, hospital-based study. Curr Clin Pharmacol 2009;4:229-32.  Back to cited text no. 22
    
23.
Jilanchi S, Nematbakhsh M, Bahadorani M, Talebi A, Eshraghi-Jazi F, Mansouri A, et al. Vitamin E is a nephroprotectant agent in male but not in female in a model of Cisplatin-induced nephrotoxicity. ISRN Nephrol 2013;2013:280395.  Back to cited text no. 23
    
24.
Eshraghi-Jazi F, Nematbakhsh M, Nasri H, Talebi A, Haghighi M, Pezeshki Z, et al. The protective role of endogenous nitric oxide donor (L-arginine) in cisplatin-induced nephrotoxicity: Gender related differences in rat model. J Res Med Sci 2011;16:1389-96.  Back to cited text no. 24
[PUBMED]  Medknow Journal  
25.
Nematbakhsh M, Pezeshki Z, Eshraghi-Jazi F, Ashrafi F, Nasri H, Talebi A, et al. Vitamin E, Vitamin C, or losartan is not nephroprotectant against Cisplatin-induced nephrotoxicity in presence of estrogen in ovariectomized rat model. Int J Nephrol 2012;2012:284896.  Back to cited text no. 25
    
26.
Nematbakhsh M, Ebrahimian S, Tooyserkani M, Eshraghi-Jazi F, Talebi A, Ashrafi F. Gender difference in Cisplatin-induced nephrotoxicity in a rat model: Greater intensity of damage in male than female. Nephrourol Mon 2013;5:818-21.  Back to cited text no. 26
    
27.
Nematbakhsh M, Nasri H. Cisplatin nephrotoxicity may be sex related. Kidney Int 2013;83:1201.  Back to cited text no. 27
    
28.
Nematbakhsh M, Talebi A, Nasri H, Safari T, Dolatkhah S, Ashrafi F. Some evidence for sex-based differences in cisplatin-induced nephrotoxicity in rats. Clin Exp Med Lett 2012;53:29-32.  Back to cited text no. 28
    
29.
Moeini M, Nematbakhsh M, Fazilati M, Talebi A, Pilehvarian AA, Azarkish F, et al. Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model. Int J Prev Med 2013;4:648-55.  Back to cited text no. 29
[PUBMED]  Medknow Journal  
30.
Mazaheri S, Nematbakhsh M, Bahadorani M, Pezeshki Z, Talebi A, Ghannadi AR, et al. Effects of fennel essential oil on Cisplatin-induced nephrotoxicity in ovariectomized rats. Toxicol Int 2013;20:138-45.  Back to cited text no. 30
[PUBMED]  Medknow Journal  
31.
Saad AA, Youssef MI, El-Shennawy LK. Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: The protective effect of grape seed proanthocyanidin extract. Food Chem Toxicol 2009;47:1499-506.  Back to cited text no. 31
    
32.
Baldew GS, McVie JG, van der Valk MA, Los G, de Goeij JJ, Vermeulen NP. Selective reduction of cis-diamminedichloroplatinum (II) nephrotoxicity by ebselen. Cancer Res 1990;50:7031-6.  Back to cited text no. 32
    
33.
Mohamed HE, El-Swefy SE, Mohamed RH, Ghanim AM. Effect of erythropoietin therapy on the progression of cisplatin induced renal injury in rats. Exp Toxicol Pathol 2013;65:197-203.  Back to cited text no. 33
    
34.
Joy J, Nair CK. Amelioration of cisplatin induced nephrotoxicity in Swiss albino mice by Rubia cordifolia extract. J Cancer Res Ther 2008;4:111-5.  Back to cited text no. 34
    
35.
Lau AH. Apoptosis induced by cisplatin nephrotoxic injury. Kidney Int 1999;56:1295-8.  Back to cited text no. 35
    
36.
Mansour HH, Hafez HF, Fahmy NM. Silymarin modulates Cisplatin-induced oxidative stress and hepatotoxicity in rats. J Biochem Mol Biol 2006;39:656-61.  Back to cited text no. 36
    
37.
Lieberthal W, Triaca V, Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: Apoptosis vs. necrosis. Am J Physiol 1996;270:F700-8.  Back to cited text no. 37
    
38.
Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: A review. Am J Med Sci 2007;334:115-24.  Back to cited text no. 38
    
39.
Helmy MM, Helmy MW, Abd Allah DM, Abo Zaid AM, Mohy El-Din MM. Selective ET (A) receptor blockade protects against cisplatin-induced acute renal failure in male rats. Eur J Pharmacol 2014;730:133-9.  Back to cited text no. 39
    
40.
Clozel M, Breu V, Gray GA, Kalina B, Löffler BM, Burri K, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther 1994;270:228-35.  Back to cited text no. 40
    
41.
Weitzberg E, Hemsén A, Rudehill A, Modin A, Wanecek M, Lundberg JM. Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock. Br J Pharmacol 1996;118:617-26.  Back to cited text no. 41
    
42.
Pezeshki Z, Nematbakhsh M, Mazaheri S, Eshraghi-Jazi F, Talebi A, Nasri H, et al. Estrogen abolishes protective effect of erythropoietin against Cisplatin-Induced nephrotoxicity in ovariectomized rats. ISRN Oncol 2012;2012:890310.  Back to cited text no. 42
    
43.
Pezeshki Z, Nematbakhsh M, Nasri H, Talebi A, Pilehvarian AA, Safari T, et al. Evidence against protective role of sex hormone estrogen in Cisplatin-induced nephrotoxicity in ovarectomized rat model. Toxicol Int 2013;20:43-7.  Back to cited text no. 43
[PUBMED]  Medknow Journal  
44.
Karet FE, Kuc RE, Davenport AP. Novel ligands BQ123 and BQ3020 characterize endothelin receptor subtypes ETA and ETB in human kidney. Kidney Int 1993;44:36-42.  Back to cited text no. 44
    
45.
Resta TC, Walker BR. Chronic hypoxia selectively augments endothelium-dependent pulmonary arterial vasodilation. Am J Physiol 1996;270:H888-96.  Back to cited text no. 45
    
46.
Förstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J 2012;33:829-37, 837a.  Back to cited text no. 46
    
47.
Bae EH, Lee J, Ma SK, Kim IJ, Frøkiaer J, Nielsen S, et al. Alpha-Lipoic acid prevents cisplatin-induced acute kidney injury in rats. Nephrol Dial Transplant 2009;24:2692-700.  Back to cited text no. 47
    
48.
Ramzy D, Rao V, Tumiati LC, Xu N, Sheshgiri R, Miriuka S, et al. Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway. Circulation 2006;114:I319-26.  Back to cited text no. 48
    
49.
Nozaki Y, Furubo E, Matsuno T, Fukui R, Kizawa K, Kozaki T, et al. Collaborative work on evaluation of ovarian toxicity 6) Two- or four-week repeated-dose studies and fertility study of cisplatin in female rats. J Toxicol Sci 2009;34 Suppl 1:SP73-81.  Back to cited text no. 49
    
50.
Harima Y, Harima K, Hasegawa T, Shikata N, Tanaka Y. Histopathological changes in rabbit uterus carcinoma after transcatheter arterial embolization using cisplatin. Cancer Chemother Pharmacol 1996;38:317-22.  Back to cited text no. 50
    
51.
Moslemi F, Nematbakhsh M, Eshraghi-Jazi F, Talebi A, Nasri H, Ashrafi F, et al. Inhibition of nitric oxide synthase by L-name promotes cisplatin-induced nephrotoxicity in male rats. ISRN Toxicol 2013;2013:242345.  Back to cited text no. 51
    
52.
Rastghalam R, Nematbakhsh M, Bahadorani M, Eshraghi-Jazi F, Talebi A, Moeini M, et al. Angiotensin type-1 receptor blockade may not protect kidney against Cisplatin-induced nephrotoxicity in rats. ISRN Nephrol 2014;2014:479645.  Back to cited text no. 52
    
53.
Stevens EJ, Tomlinson DR. Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes. Br J Pharmacol 1995;115:373-9.  Back to cited text no. 53
    
54.
Seibold JR, Denton CP, Furst DE, Guillevin L, Rubin LJ, Wells A, et al. Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis. Arthritis Rheum 2010;62:2101-8.  Back to cited text no. 54
    
55.
Nakano D, Pollock JS, Pollock DM. Renal medullary ETB receptors produce diuresis and natriuresis via NOS1. Am J Physiol Renal Physiol 2008;294:F1205-11.  Back to cited text no. 55