Changes in the serum, liver, and renal cortical lipids and electrolytes in rabbits with cisplatin-induced nephrotoxicity

Changes in the serum, liver, and renal cortical lipids and electrolytes in rabbits with cisplatin-induced nephrotoxicity

Background/aim: Cisplatin is an anticancer drug that can induce nephrotoxicity. Its toxicity is associated with dyslipidemia and disturbed electrolyte balance. In the present study we investigated the changes in serum lipid profile and electrolyte levels and their contents in kidney and liver tissues of rabbits treated with cisplatin. Materials and methods: Twenty-eight adult male New Zealand White rabbits were used in the experiment. Animals of groups C, P1, and P2 were injected with saline, cisplatin (4.0 mg/kg bw), and cisplatin (6.5 mg/kg bw), respectively, and killed 3 days after the injections. Animals of group R were given cisplatin (6.5 mg/kg bw) and killed after 7 days. All animals were killed after an overnight fast. Results: The P2 animals showed reductions in their body weights, significant (P < 0.001) increases in serum creatinine and urea levels, and significant (P < 0.001) drops in cortical alkaline phosphatase activity and necrotic kidney histology. The treatments had no effect on liver function. Moreover, the P2 animals showed increased serum cholesterol, TAG, and elevated LDL-cholesterol, with significant accumulations of the kidney cholesterol and TAG, but no change in serum phospholipid and depleted hepatic cholesterol. Moreover, the P2 animals had depressed serum levels of potassium, calcium, and magnesium, and reduced renal cortical calcium and magnesium contents and depressed liver calcium but not magnesium. However, the P1 animals had no significant alterations in their lipid or electrolyte levels. Most of the perturbed parameters returned to normal levels in the recovery group. Conclusion: Cisplatin nephrotoxicity in rabbits is accompanied by reductions in body weight, secondary dyslipidemia, and reduced serum potassium, calcium, and magnesium with depleted renal cortical magnesium and calcium and accumulated cortical lipids.

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  • 1. Boulikas T. Molecular mechanisms of cisplatin and its liposomally encapsulated form, lipoplatin. Lipoplatin as a chemotherapy and antiangiogenesis drug. Cancer Ther 2007; 5: 349-376
  • 2. Perez RP. Cellular and molecular determinants of cisplatin resistance. Eur J Cancer 1998; 34: 1535- 1542.
  • 3. Hanigan MH, Devarajan P. Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 2003; 1: 47-61.
  • 4. Kuhlmann MK, Burkhardt G, Kohler H. Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application.  Nephrol Dial Transplant  1997;  12: 2478- 2480.
  • 5. Santos NAG,  Catão CS, Martins NM, Curti C,  Bianchi MLP,  Santo 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.
  • 6. Friedewald  WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
  • 7. Barlett, GR. Phosphorus assay in column chromatography. J Biol Chem 1959; 234: 466-468.
  • 8. Lowry OH, Rosebrough NJ, Fair AI, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275.
  • 9. Clark WF. Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney Int 1993; 44: 75-86.
  • 10. Abdel-Gayoum AA, El-Jenjan KB, Ghwarsha KA. Hyperlipidaemia in cisplatin-induced nephrotic rats. Human Exp Toxicol 1999; 18: 454-459.
  • 11. Liu M, Chien CC, Burne-Taney M, Molls RR, Racusen LC, Colvin RB, Rabb H. A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. J Am Soc Nephrol 2006; 17: 765-774.
  • 12. Ishikawa T, Bao JJ, Yamane Y, Akimaru K, Frindrich K, Wright CD, Kuo MT. Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 1996; 271: 14981-14988. 
  • 13. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins.  J Natl Cancer Inst 2000; 92: 1295-1302. 
  • 14. Hadjzadeh MA, Rajaei Z, Keshavarzi Z, Shirazi MG, Toosi V. Effect of aqueous extract of Rheum ribes on cisplatin-induced nephrotoxicity in rat. J Pharm Bioallied Sci 2013; 5: 309-313.
  • 15. Abdel-Gayoum AA, Ali BH, Ghwarsha K, Bashir AA. Plasma lipid profiles in the rat with gentamicin-induced nephrotoxicity. Human Exp Toxicol 1993; 12: 371-378.
  • 16. Abdel-Gayoum AA, Alhasan AA, Ginawi I, Alshankyty IM. The ameliorative effect of olive oil and olive leaf extract on the amikacin-induced nephrotoxicity in the rat. Toxicol Report 2015; 2: 1327-1333.
  • 17. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
  • 18. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
  • 19. Jerlich A, Pitt AR, Schaur RJ, Spickett CM. Pathways of phospholipid oxidation by HOCl in human LDL detected by LC-MS. Free Radic Biol Med 2000; 28: 673-682.
  • 20. Subbanagounder G, Leitinger N, Schwenke D, Wong J W, Lee H, Rizza C, Watson A D, Faull KF, Fogelman AM, Berliner JA. Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position. Thromb Vasc Biol 2000; 20: 2248-2254.
  • 21. Berliner JA, Subbanagounder G, Leitinger N, Watson AD, Vora D. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc Med 2001; 11: 142-147.
  • 22. Bochkov V N, Mechtcheriakova D, Lucerna M, Huber J, Malli R, Graier WF, Hofer E, Binder B, Leitinger N. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/ NFAT. Blood 2002; 99: 199-206.
  • 23. Coimbra  TM,  Janssen U,  Grone HJ,  Ostendorf T,  Kunter U, Schmidt H, Brabant G, Floege J. Early events leading to renal injury in obese Zucker fatty rats with type II diabetes. Kidney Int 2000; 57: 167-182.
  • 24. Gevorgyn ES, Hovhanisyan AG, Yavroyan ZH, Hakobyan NR, Sargsyan EG. Cisplatin in vivo action on content of neutral lipids in rat liver and thymus nuclear membranes. Biological Journal of Armenia 2013; 2: 99-103.
  • 25. Reade V, Tailleux A, Reade R. Expression of apolipoprotein B epitopes in low density lipoproteins of hemodialyzed patients. Kidney Int 1993; 44: 1360-1365.
  • 26. Kramer A, Nauck M, Pavenstad H, Schwedler S, Wieland H, Schollmeyer P, Wanner C. Receptor-mediated uptake of IDL and LDL from nephrotic patients by glomerular epithelial cells. Kidney Int 1993; 44: 1341-1351.
  • 27. Bodnar L, Wcislo G, Gasowska-Bodnar A, Synowiec A, SzarlejWcislo K. Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study. Eur J Cancer 2008; 44: 2608-2614.
  • 28. Willox JC, McAllister EJ, Sangster G, Kaye SB. Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a randomised trial. Br J Cancer 1986; 54: 19-23.
  • 29. Sahin AA, Oysu C, Yilmaz HB, Topak M, Kulekci M, Okar I. Effect of oral magnesium supplementation on cisplatin ototoxicity. J Otolaryngol 2006; 35: 112-116.
  • 30. van Angelen AA, Glaudemans B, van der Kemp AW, Hoenderop J, Bindels RJ. Cisplatin-induced injury of the renal distal convoluted tubule is associated with hypomagnesaemia in mice. Nephrol Dial Transplant 2013; 28: 879-889.
  • 31. Lajer H1, Kristensen M, Hansen HH, Nielsen S, Frøkiaer J, Ostergaard LF, Christensen S, Daugaard G, Jonassen TE. Magnesium depletion enhances cisplatin-induced nephrotoxicity. Cancer Chemother Pharmacol 2005; 56: 535- 542.
  • 32. Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev 1999; 25: 47-58.
  • 33. Ciarimboli G, Ludwig T, Lang D, Pavenstadt H, Koepsell H, Koepsell H, Piechota HJ, Haier J, Jaehde U, Zisowsky J et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 2005; 167: 1477- 1484.
  • 34. Yokoo K, Murakami R, Matsuzaki T, Yoshitome K, Hamada A, Saito H. Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats. Clin Exp Nephrol 2009; 13: 578-584.
  • 35. Marklund L, Andersson B, Behnam-Motlagh P, Sandstrom P, Henriksson R, Grankvist K. Cellular potassium ion deprivation enhances apoptosis induced by cisplatin. Basic Clin Pharm Toxicol 2004; 94: 245-251.
  • 36. Karimzadeh I, Hossein Khalili H, Dashti-Khavidaki S, Sharifian R, Abdollahi A, Hasibi M, Khazaeipour Z, Farsaei S. N-acetyl cysteine in prevention of amphotericin-induced electrolytes imbalances: a randomized, double-blinded, placebo-controlled, clinical trial. Eur J Clin Pharmacol 2014; 70: 399-408.
  • 37. Pere AK,  Lindgren L,  Tuomainen P,  Krogerus L, Rauhala P, Laakso J, Karppanen H, Vapaatalo H, Ahonen J, Mervaala EM. Dietary potassium and magnesium supplementation in cyclosporine-induced hypertension and nephrotoxicity. Kidney Int 2000; 58: 2462-2472.
  • 38. Maheshwari RA, Sailor GU, Patel L, Balaraman R. Amelioration of cisplatin-induced nephrotoxicity by statins. Indian J Pharmacol 2013; 45: 354-358.
  • 39. Patil AN, Arora T, Desai A, Tripathi CD. Comparison of the species-sensitive effects of different dosages of calcium and verapamil on gentamicin-induced nephrotoxicity in rats and rabbits. Toxicol Int 2014; 21: 225-231.
Turkish Journal of Medical Sciences-Cover
  • ISSN: 1300-0144
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK