Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference


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

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

3 Water and Electrolytes Research Center; Department of Clinical Pathology, Isfahan University of Medical Sciences, Isfahan, Iran


Background: The function of renin angiotensin system (RAS) is gender-related, and this system affects cisplatin (CP)-induced nephrotoxicity. In this study, we compared the effect of enalapril as an angiotensin-converting enzyme (ACE) inhibitor on CP-induced nephrotoxicity between male and female rats.
Materials and Methods: Sixty-two adult male and female Wistar rats were divided into eight groups. Both genders received CP (2.5 mg/kg, i.p.) and enalapril (30 mg/kg, i.p.) for 7 days in compared with CP alone or enalapril alone or vehicle alone treated groups. At the end of the experiment, blood samples were obtained, and the kidney tissue was investigated for histopathological changes.
Results: CP increased the serum levels of blood urea nitrogen and creatinine as well as kidney weight and kidney tissue damage score in both genders (P < 0.05). However, not only enalapril failed to ameliorate the aforementioned parameters in both genders, but also it intensified nephrotoxicity in females (P < 0.05).In addition, enalapril enhanced body weight loss induced by CP in females (P < 0.05). CP alone decreased kidney level of nitrite in both genders (P < 0.05) and enalapril could not reverse this decreasing. The combination of enalapril and CP significantly increased serum level of nitrite in females, but this was not observed in males (P < 0.05).
Conclusion: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.


Bagatell R, Beliakoff J, David CL, Marron MT, Whitesell L. Hsp90 inhibitors deplete key anti-apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin. Int J Cancer 2005;113:179-88.  Back to cited text no. 1
Bergamo A, Gagliardi R, Scarcia V, Furlani A, Alessio E, Mestroni G, et al. In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin. J Pharmacol Exp Ther 1999;289:559-64.  Back to cited text no. 2
Ries F, Klastersky J. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 1986;8:368-79.  Back to cited text no. 3
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. 4
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. 5
[PUBMED]  Medknow Journal  
Ali B, Ismail TB, Bashir A. Sex difference in the susceptibility of rats to gentamicin nephrotoxicity: Influence of gonadectomy and hormonal replacement therapy. Indian J Pharmacol 2001;33:369-73.  Back to cited text no. 6
  Medknow Journal  
Bennett WM, Parker RA, Elliott WC, Gilbert DN, Houghton DC. Sex-related differences in the susceptibility of rats to gentamicin nephrotoxicity. J Infect Dis 1982;145:370-3.  Back to cited text no. 7
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. 8
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. 9
Nematbakhsh M, Nasri H. Cisplatin nephrotoxicity may be sex related. Kidney Int 2013;83:1201.  Back to cited text no. 10
Nematbakhsh M, Pezeshki Z. Sex-related difference in nitric oxide metabolites levels after nephroprotectant supplementation administration against cisplatin-induced nephrotoxicity in wistar rat model: The role of Vitamin E, erythropoietin, or n-acetylcysteine. ISRN Nephrol 2013;2013:612675.  Back to cited text no. 11
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. 12
[PUBMED]  Medknow Journal  
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. 13
Haghighi M, Nematbakhsh M, Talebi A, Nasri H, Ashrafi F, Roshanaei K, et al. The role of angiotensin II receptor 1 (AT1) blockade in cisplatin-induced nephrotoxicity in rats: Gender-related differences. Ren Fail 2012;34:1046-51.  Back to cited text no. 14
Eshraghi-Jazi F, Nematbakhsh M, Pezeshki Z, Nasri H, Talebi A, Safari T, et al. Sex differences in protective effect of recombinant human erythropoietin against cisplatin-induced nephrotoxicity in rats. Iran J Kidney Dis 2013;7:383-9.  Back to cited text no. 15
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. 16
McFarlane SI, Kumar A, Sowers JR. Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol 2003;91:30H-7.  Back to cited text no. 17
Omata K, Kanazawa M, Sato T, Abe F, Saito T, Abe K. Therapeutic advantages of angiotensin converting enzyme inhibitors in chronic renal disease. Kidney Int Suppl 1996;55:S57-62.  Back to cited text no. 18
Chopra M, Beswick H, Clapperton M, Dargie HJ, Smith WE, McMurray J. Antioxidant effects of angiotensin-converting enzyme (ACE) inhibitors: Free radical and oxidant scavenging are sulfhydryl dependent, but lipid peroxidation is inhibited by both sulfhydryl- and nonsulfhydryl-containing ACE inhibitors. J Cardiovasc Pharmacol 1992;19:330-40.  Back to cited text no. 19
Vidhya R, Thi MJ, Agavalli U. Protective effect of captopril against cisplatin induced nephrotoxicity in rats. Pharmacol Online 2010;1:12-5.  Back to cited text no. 20
El-Sayed el-SM, Abd-Ellah MF, Attia SM. Protective effect of captopril against cisplatin-induced nephrotoxicity in rats. Pak J Pharm Sci 2008;21:255-61.  Back to cited text no. 21
Keith DS, Torres VE, Johnson CM, Holley KE. Effect of sodium chloride, enalapril, and losartan on the development of polycystic kidney disease in Han: SPRD rats. Am J Kidney Dis 1994;24:491-8.  Back to cited text no. 22
Hilliard LM, Nematbakhsh M, Kett MM, Teichman E, Sampson AK, Widdop RE, et al. Gender differences in pressure-natriuresis and renal autoregulation: Role of the angiotensin type 2 receptor. Hypertension 2011;57:275-82.  Back to cited text no. 23
Pezeshki Z, Eshraghi-Jazi F, Nematbakhsh M. Vascular response to graded angiotensin II infusion in offspring subjected to high-salt drinking water during pregnancy: The effect of blood pressure, heart rate, urine output, endothelial permeability, and gender. Int J Vasc Med 2014;2014:876527.  Back to cited text no. 24
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. 25
[PUBMED]  Medknow Journal  
Nematbakhsh M, Safari T. Role of Mas receptor in renal blood flow response to angiotensin (1-7) in male and female rats. Gen Physiol Biophys 2014;33:365-72.  Back to cited text no. 26
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. 27
Zapater P, Novalbos J, Gallego-Sandín S, Hernández FT, Abad-Santos F. Gender differences in angiotensin-converting enzyme (ACE) activity and inhibition by enalaprilat in healthy volunteers. J Cardiovasc Pharmacol 2004;43:737-44.  Back to cited text no. 28
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. 29
Yamate J, Sato K, Machida Y, Ide M, Sato S, Nakatsuji S, et al. Cisplatin-induced rat renal interstitial fibrasis; a possible pathogenesis based on the data. J Toxicol Pathol 2000;13:237-47.  Back to cited text no. 30
Hannemann J, Baumann K. Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: Different effects of antioxidants and radical scavengers. Toxicology 1988;51:119-32.  Back to cited text no. 31
Herlitz H, Svalander C, Tarkowski A, Westberg G. Effect of captopril on murine systemic lupus erythematosus disease. J Hypertens Suppl 1988;6:S684-6.  Back to cited text no. 32
Pechanova O. Contribution of captopril Thiol group to the prevention of spontaneous hypertension. Physiol Res Acad Sci Bohemoslov 2007;56 Suppl 2:S41-8.  Back to cited text no. 33
Ohishi A, Suzuki H, Nakamoto H, Katsumata H, Sakaguchi H, Saruta T. Differences in the effects of angiotensin converting enzyme inhibitors with or without a thiol group in chronic renal failure in rats. Clin Sci (Lond) 1989;76:353-6.  Back to cited text no. 34
Lassila M, Finckenberg P, Pere AK, Krogerus L, Ahonen J, Vapaatalo H, et al. Comparison of enalapril and valsartan in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet. Br J Pharmacol 2000;130:1339-47.  Back to cited text no. 35
Azzadin A, Malyszko J, Malyszko JS, Tankiewicz A, Mysliwiec M, Buczko W. Effects of combination of cyclosporine with losartan or enalapril on kidney function in uremic rats. Pol J Pharmacol 2002;54:469-73.  Back to cited text no. 36
Guron G. Renal haemodynamics and function in weanling rats treated with enalapril from birth. Clin Exp Pharmacol Physiol 2005;32:865-70.  Back to cited text no. 37
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. 38
[PUBMED]  Medknow Journal  
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. 39
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. 40
Dean SA, Tan J, O'Brien ER, Leenen FH. 17beta-estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats. Am J Physiol Regul Integr Comp Physiol 2005;288:R759-66.  Back to cited text no. 41
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. 42
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. 43
[PUBMED]  Medknow Journal  
Ohno T, Kato S, Wakatsuki M, Noda SE, Murakami C, Nakamura M, et al. Incidence and temporal pattern of anorexia, diarrhea, weight loss, and leukopenia in patients with cervical cancer treated with concurrent radiation therapy and weekly cisplatin: Comparison with radiation therapy alone. Gynecol Oncol 2006;103:94-9.  Back to cited text no. 44
Santos EL, de Picoli Souza K, Guimarães PB, Reis FC, Silva SM, Costa-Neto CM, et al. Effect of angiotensin converting enzyme inhibitor enalapril on body weight and composition in young rats. Int Immunopharmacol 2008;8:247-53.  Back to cited text no. 45
Leung EL, Fraser M, Fiscus RR, Tsang BK. Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: Involvement in p53 regulation and cisplatin resistance. Br J Cancer 2008;98:1803-9.  Back to cited text no. 46
Ohwada T, Ishibashi T, Yaoita H, Shindo J, Noji H, Ohkawara H, et al. Different contribution of apoptosis to the antiproliferative effects of L-arginine, enalapril and losartan on neointimal growth inhibition after balloon arterial injury. Circ J 2002;66:965-71.  Back to cited text no. 47
Pezeshki Z, Nematbakhsh M. Nitric oxide metabolites change in cisplatin-induced nephrotoxicity: The effect of L-arginine and losartan. J Anal Oncol 2013;2:117-9.  Back to cited text no. 48
Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol Res 2007;55:81-95.  Back to cited text no. 49