open access
The possible protective effect of L-arginine against 5-fluorouracil-induced nephrotoxicity in male albino rats
open access
Abstract
5-fluorouracil (5-FU) is a potent antineoplastic agent used for the treatment of various malignancies. The L-arginine nitric oxide (NO) pathway involved in the pathogenesis of chemotherapy induced kidney damage. This work investigated the beneficial mechanism of L-arginine supplementation in 5-FU induced nephropathy. Eighty male Wistar rats were divided into four equal groups: control group; L-arginine group (378 mg/rat/day for 4 weeks); 5-FU group (189 mg/rat/week for 4 weeks) and L-arginine for 1 week before and 4 weeks concomitant with 5-FU group. At the end of experiment, the kidney functions were assessed and kidneys specimens were processed for paraffin sections and stained with haematoxylin and eosin (H&E), Masson’s trichome (MT) and periodic acid-Schiff (PAS) stains. Other sections were processed for immunohistochemical demonstration of caspase-3 and inducible NO synthase (iNOS). Image analyser was used to analyse the results morphometrically and statistically. L-arginine administration to 5-FU treated animals elicited significant reduction in serum urea and creatinine levels, urine volume, urinary protein excretion and kidney/body weight ratio in comparison to fluorouracil treated group. L-arginine improved glomeruloscelerosis, degeneration of convoluted tubules and interstitial fibrosis in 5-FU treated animals. L-arginine attenuated effectively some biochemical and histological changes in 5-FU nephrotoxicity.
Abstract
5-fluorouracil (5-FU) is a potent antineoplastic agent used for the treatment of various malignancies. The L-arginine nitric oxide (NO) pathway involved in the pathogenesis of chemotherapy induced kidney damage. This work investigated the beneficial mechanism of L-arginine supplementation in 5-FU induced nephropathy. Eighty male Wistar rats were divided into four equal groups: control group; L-arginine group (378 mg/rat/day for 4 weeks); 5-FU group (189 mg/rat/week for 4 weeks) and L-arginine for 1 week before and 4 weeks concomitant with 5-FU group. At the end of experiment, the kidney functions were assessed and kidneys specimens were processed for paraffin sections and stained with haematoxylin and eosin (H&E), Masson’s trichome (MT) and periodic acid-Schiff (PAS) stains. Other sections were processed for immunohistochemical demonstration of caspase-3 and inducible NO synthase (iNOS). Image analyser was used to analyse the results morphometrically and statistically. L-arginine administration to 5-FU treated animals elicited significant reduction in serum urea and creatinine levels, urine volume, urinary protein excretion and kidney/body weight ratio in comparison to fluorouracil treated group. L-arginine improved glomeruloscelerosis, degeneration of convoluted tubules and interstitial fibrosis in 5-FU treated animals. L-arginine attenuated effectively some biochemical and histological changes in 5-FU nephrotoxicity.
Keywords
L-arginine, nephrotoxicity, 5-fluorouracil
About this articleTitle
The possible protective effect of L-arginine against 5-fluorouracil-induced nephrotoxicity in male albino rats
Journal
Issue
Article type
Original article
Pages
608-619
Published online
2017-04-19
Page views
1800
Article views/downloads
1996
DOI
Pubmed
Bibliographic record
Folia Morphol 2017;76(4):608-619.
Keywords
L-arginine
nephrotoxicity
5-fluorouracil
Authors
M. H. Badawoud
E. B. Elshal
A. I. Zaki
H. A. Amin
References (46)- Abo Zeid AA, El Saka MH, Shafik NM. Effect of combination of l-arginine and n-acetyl cysteine in rat model of renal ischemia-reperfusion injury. J Am Sci. 2012; 8(10): 814–921.
- Adejuwon A, Femi-Akinlosotu O, Omirinde JO, et al. Launaea taraxacifolia Ameliorates Cisplatin-Induced Hepato-renal Injury. Eur J Med Plants. 2014; 4(5): 528–541.
- Aiello S, Noris M, Todeschini M, et al. Renal and systemic nitric oxide synthesis in rats with renal mass reduction. Kidney Int. 1997; 52(1): 171–181.
- Ali BH, Al Moundhri MS. Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Chem Toxicol. 2006; 44(8): 1173–1183.
- Amore A, Gianoglio B, Ghigo D, et al. A possible role for nitric oxide in modulating the functional cyclosporine toxicity by arginine. Kidney Int. 1995; 47(6): 1507–1514.
- Ashab I, Peer G, Blum M, et al. Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int. 1995; 47(6): 1515–1521.
- Bancroft JD, Cook HC. Immunohistochemical staining by standard avidin-biotin-peroxidase method. In: Bancroft JD, Cook HC. ed. Manual of histological techniques. Churchill, Livingstone 1984: 195–202.
- Bancroft JD, Gamble M. Theory and practice of histological techniques. 5th ed. Churchill, Livingstone 2001: 173–175.
- Bank N, Aynedjian HS, Qiu JH, et al. Renal nitric oxide synthases in transgenic sickle cell mice. Kidney Int. 1996; 50(1): 184–189.
- Bidadkosh A, Derakhshanfar A, Rastegar A, et al. Antioxidant preserving effects of l-arginine at reducing the hemodynamic toxicity of gentamicin-induced rat nephrotoxicity: pathological and biochemical findings. Comparative Clinical Pathology. 2012; 21(6): 1739–1744.
- Braga-Neto MB, Warren CA, Oriá RB, et al. Alanyl-glutamine and glutamine supplementation improves 5-fluorouracil-induced intestinal epithelium damage in vitro. Dig Dis Sci. 2008; 53(10): 2687–2696.
- Bremer V, Tojo A, Kimura K, et al. Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase. J Am Soc Nephrol. 1997; 8(11): 1712–1721.
- Cabellos R, Garcia-Carbonero R, Garcia-Lacalle C, et al. Fluorouracil-based chemotherapy in patients with gastrointestinal malignancies: influence of nutritional folate status on toxicity. J Chemother. 2007; 19(6): 744–749.
- Can C, Sen S, Boztok N, et al. Protective effect of oral L-arginine administration on gentamicin-induced renal failure in rats. Eur J Pharmacol. 2000; 390(3): 327–334.
- Chatterjee PK, Patel NSA, Kvale EO, et al. Inhibition of inducible nitric oxide synthase reduces renal ischemia/reperfusion injury. Kidney Int. 2002; 61(3): 862–871.
- Cherla G, Jaimes EA. Role of L-arginine in the pathogenesis and treatment of renal disease. J Nutr. 2004; 134(10 Suppl): 2801S–2806S; discussion 2818S.
- Coers W, Timens W, Kempinga C, et al. Specificity of antibodies to nitric oxide synthase isoforms in human, guinea pig, rat, and mouse tissues. J Histochem Cytochem. 1998; 46(12): 1385–1392.
- Cool JC, Dyer JL, Xian CJ, et al. Pre-treatment with insulin-like growth factor-I partially ameliorates 5-fluorouracil-induced intestinal mucositis in rats. Growth Horm IGF Res. 2005; 15(1): 72–82.
- Devlin TM. Text book of biochemistry: with clinical correlation, 4th ed. John Wiley and Sons Inc, New York 1997: 553–560.
- El-Hoseany NMA. Protective effect of captopril against 5-fluorouracil-induced hepato and nephrotoxicity in male Albino rats. J Am Sci. 2012; 8(2): 680–685.
- El-Sayed eS, Abd-Ellah MF, Attia SM. Protective effect of captopril against cisplatin-induced nephrotoxicity in rats. PakJ. Pharm Sci. 2008; 21(3): 255–261.
- Fujihara CK, Mattar AL, Vieira JM, et al. Evidence for the existence of two distinct functions for the inducible NO synthase in the rat kidney: effect of aminoguanidine in rats with 5/6 ablation. J Am Soc Nephrol. 2002; 13(9): 2278–2287.
- Hayashi T, Matsui-Hirai H, Fukatsu A, et al. Selective iNOS inhibitor, ONO1714 successfully retards the development of high-cholesterol diet induced atherosclerosis by novel mechanism. Atherosclerosis. 2006; 187(2): 316–324.
- Heeringa P, van Goor H, Moshage H, et al. Expression of iNOS, eNOS, and peroxynitrite-modified proteins in experimental anti-myeloperoxidase associated crescentic glomerulonephritis. Kidney Int. 1998; 53(2): 382–393.
- Isaka Y, Rakugi H. Severe adverse effects of 5-fluorouracil in S-1 were lessened by haemodialysis due to elimination of the drug. NDT Plus. 2009; 2(2): 152–154.
- Ito K, Chen J, Vaughan ED, et al. Dietary L-arginine supplementation improves the glomerular filtration rate and renal blood flow after 24 hours of unilateral ureteral obstruction in rats. J Urol. 2004; 171(2 Pt 1): 926–930.
- Joles JA, Vos IH, Gröne HJ, et al. Inducible nitric oxide synthase in renal transplantation. Kidney Int. 2002; 61(3): 872–875.
- Kakoki M, Kim HS, Arendshorst WJ, et al. L-Arginine uptake affects nitric oxide production and blood flow in the renal medulla. Am J Physiol Regul Integr Comp Physiol. 2004; 287(6): R1478–R1485.
- Lin Y, Wang LN, Xi YH, et al. L-arginine inhibits isoproterenol-induced cardiac hypertrophy through nitric oxide and polyamine pathways. Basic Clin Pharmacol Toxicol. 2008; 103(2): 124–130.
- Ling H, Edelstein C, Gengaro P, et al. Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. Am J Physiol. 1999; 277(3 Pt 2): F383–F390.
- Mansour M, Daba MH, Gado A, et al. Protective effect of L-arginine against nephrotoxicity induced by cyclosporine in normal rats. Pharmacol Res. 2002; 45(6): 441–446.
- Miller AA, Megson IL, Gray GA. Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure. Br J Pharmacol. 2000; 131(1): 29–36.
- Raij L, Baylis C. Glomerular actions of nitric oxide. Kidney Int. 1995; 48(1): 20–32.
- Rashid S, Ali N, Nafees S, et al. Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats. Food Chem Toxicol. 2014; 66: 185–193.
- Romero F, Rodríguez-Iturbe B, Parra G, et al. Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int. 1999; 55(3): 945–955.
- Rusai K, Fekete A, Szebeni B, et al. Effect of inhibition of neuronal nitric oxide synthase and L-arginine supplementation on renal ischaemia-reperfusion injury and the renal nitric oxide system. Clin Exp Pharmacol Physiol. 2008; 35(10): 1183–1189.
- Saleh S, El-Demerdash E. Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity: role of nitric oxide. Basic Clin Pharmacol Toxicol. 2005; 97(2): 91–97.
- Schneider R, Raff U, Vornberger N, et al. L-Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats. Kidney Int. 2003; 64(1): 216–225.
- Schramm L, La M, Heidbreder E, et al. L-arginine deficiency and supplementation in experimental acute renal failure and in human kidney transplantation. Kidney Int. 2002; 61(4): 1423–1432.
- Schwartz D, Mendonca M, Schwartz I, et al. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest. 1997; 100(2): 439–448.
- Sharma SP. Nitric oxide and the kidney. Indian J Nephrol. 2004; 14(3): 77–84.
- Silverstein RA, González de Valdivia E, Visa N. The incorporation of 5-fluorouracil into RNA affects the ribonucleolytic activity of the exosome subunit Rrp6. Mol Cancer Res. 2011; 9(3): 332–340.
- Thant AA, Wu Y, Lee J, et al. Role of caspases in 5-FU and selenium-induced growth inhibition of colorectal cancer cells. Anticancer Res. 2008; 28: 3579–3592.
- Vaziri ND, Ni Z, Wang XQ, et al. Down-regulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH. Am J Physiol. 1998; 274(4 Pt 2): F642–F649.
- Xia Y, Roman LJ, Masters BS, et al. Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem. 1998; 273(35): 22635–22639.
- Xian CJ, Howarth GS, Cool JC, et al. Effects of acute 5-fluorouracil chemotherapy and insulin-like growth factor-I pretreatment on growth plate cartilage and metaphyseal bone in rats. Bone. 2004; 35(3): 739–749.
