The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury

Zarife Özdemir Kumral; Alisina Bulut; Bahadır Üzülmez; Mustafa Vezirhüyük; Zafer Kök; Naziye Özkan Yenal; Berrak Yegen; Mehmet Koç

The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury

Abstract

Cisplatin (CP), which is the most commonly used anticancer agent to treat several solid tumors, may cause acute kidney injury (AKI) as the major limiting factor for its clinical use. Obestatin (OB) is a ghrelin gene-derived peptide produced in several tissues and has shown anti-oxidant, anti-apoptotic, and anti-inflammatory effects in many experimental models. This study investigated the effect of OB treatment on nephrotoxicity induced by CP. Rats were divided into 4 groups as two control (1 ml/kg, saline, intraperitoneal (ip), single dose) and two CP-induced (7 mg/kg, ip, single dose) AKI groups (8 rats in each group). Immediately after the CP injection and the following two days, injections of OB (10 μg/kg, ip) were performed. Rats were decapitated at the end of 72 hours. Blood and kidney tissue samples were taken for biochemical and histopathological measurements. The results of the present study revealed that serum creatinine and BUN levels were significantly increased in the CP-induced AKI group when compared to the control group. Treatment with OB improved kidney functions and ameliorated renal oxidative injury and maintained oxidative balance in the CP-induced AKI model, which was revealed by elevated malondialdehyde and depleted glutathione levels. TUNEL scores also demonstrated that CP increased the apoptotic response, while OB treatment abolished it. CP-induced medullary and cortical injuries were also partially reversed by OB treatment. Thus, our findings show that OB alleviates CP-induced nephrotoxicity in rats through the abolishment of oxidative stress and apoptosis.

Keywords

References

1. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. May 2008;73(9):994-1007. [CrossRef]
2. Kintzel PE. Anticancer drug-induced kidney disorders. Drug Saf. Jan 2001;24(1):19-38. [CrossRef]
3. Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. Feb 2007;33(1):9-23. [CrossRef]
4. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. Aug 2007;334(2):115-24. [CrossRef]
5. Hegazy MG, Emam MA. Ethanolic extract of Trigonella Foenum Graecum attenuates cisplatin-induced nephro- and hepatotoxicities in rats. Cell Mol Biol (Noisy-le-grand). Nov 25 2015;61(7):81-7.
6. Martins NM, Santos NA, Curti C, Bianchi ML, Santos AC. Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. J Appl Toxicol. Apr 2008;28(3):337-44. [CrossRef]
7. Hajian S, Rafieian-Kopaei M, Nasri H. Renoprotective effects of antioxidants against cisplatin nephrotoxicity. J Nephropharmacol. 2014;3(2):39-42.
8. Zhang JV, Ren PG, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science. Nov 11 2005;310(5750):996-9. [CrossRef]

9. Aydin S, Ozkan Y, Erman F, et al. Presence of obestatin in breast milk: relationship among obestatin, ghrelin, and leptin in lactating women. Nutrition. Jul-Aug 2008;24(7-8):689-93. [CrossRef]
10. Bang AS, Soule SG, Yandle TG, Richards AM, Pemberton CJ. Characterisation of proghrelin peptides in mammalian tissue and plasma. J Endocrinol. Feb 2007;192(2):313-23. [CrossRef]
11. Chanoine JP, Wong AC, Barrios V. Obestatin, acylated and total ghrelin concentrations in the perinatal rat pancreas. Horm Res. 2006;66(2):81-8. [CrossRef]
12. Gronberg M, Tsolakis AV, Magnusson L, Janson ET, Saras J. Distribution of obestatin and ghrelin in human tissues: immunoreactive cells in the gastrointestinal tract, pancreas, and mammary glands. J Histochem Cytochem. Sep 2008;56(9):793-801. [CrossRef]
13. Stempniewicz A, Ceranowicz P, Warzecha Z. Potential Therapeutic Effects of Gut Hormones, Ghrelin and Obestatin in Oral Mucositis. Int J Mol Sci. Mar 27 2019;20(7). [CrossRef]
14. Ozbay Y, Aydin S, Dagli AF, et al. Obestatin is present in saliva: alterations in obestatin and ghrelin levels of saliva and serum in ischemic heart disease. BMB Rep. Jan 31 2008;41(1):55-61. [CrossRef]
15. Li ZF, Guo ZF, Cao J, et al. Plasma ghrelin and obestatin levels are increased in spontaneously hypertensive rats. Peptides. Feb 2010;31(2):297-300. [CrossRef]
16. Penna C, Tullio F, Femmino S, et al. Obestatin regulates cardiovascular function and promotes cardioprotection through the nitric oxide pathway. J Cell Mol Med. Dec 2017;21(12):3670-3678. [CrossRef]
17. Ersahin M, Ozsavci D, Sener A, et al. Obestatin alleviates subarachnoid haemorrhage-induced oxidative injury in rats via its anti-apoptotic and antioxidant effects. Brain Inj. 2013;27(10):1181-9. [CrossRef]
18. Koc M, Kumral ZN, Ozkan N, et al. Obestatin improves ischemia/reperfusion-induced renal injury in rats via its antioxidant and anti-apoptotic effects: role of the nitric oxide. Peptides. Oct 2014;60:23-31. [CrossRef]
19. Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med. May 1963;61:882-8.
20. Luo J, Tsuji T, Yasuda H, Sun Y, Fujigaki Y, Hishida A. The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats. Nephrol Dial Transplant. Jul 2008;23(7):2198-205. [CrossRef]
21. Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol. Sep 2003;23(5):460-4. [CrossRef]
22. Lieberthal W, Triaca V, Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol. Apr 1996;270(4 Pt 2):F700-8. [CrossRef]
23. Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M. Relationship of intracellular calcium and oxygen radicals to Cisplatin-related renal cell injury. J Pharmacol Sci. Jan 2006;100(1):65-72. [CrossRef]
24. Badary OA, Abdel-Maksoud S, Ahmed WA, Owieda GH. Naringenin attenuates cisplatin nephrotoxicity in rats. Life Sci. Mar 18 2005;76(18):2125-35. [CrossRef]
25. Aragno M, Cutrin JC, Mastrocola R, Perrelli MG, Restivo F, Poli G, et al. Oxidativestress and kidney dysfunction due to ischemia/reperfusion in rat: attenuationby dehydroepiandrosterone. Kidney Int 2003;64:836–43.
26. Pamukcu O, Kumral ZN, Ercan F, Yegen BC, Ertem D. Anti-inflammatory effect ofobestatin and ghrelin in dextran sulfate sodium-induced colitis in rats. J PediatrGastroenterol Nutr 2013;57:211–8.
27. Granata R, Settanni F, Gallo D, et al. Obestatin promotes survival of pancreatic beta-cells and human islets and induces expression of genes involved in the regulation of beta-cell mass and function. Diabetes. Apr 2008;57(4):967-79. [CrossRef]
28. Michael S. Goligorsky, Sergey V. Brodsky, Eisei Noiri, Nitric oxide in acute renal failure: NOS versus NOS, Kidney International, 2002; 61(3): 855-861. [CrossRef]
29. Sen LS, Karakoyun B, Yegen C, et al. Treatment with either obestatin or ghrelin attenuates mesenteric ischemia-reperfusion-induced oxidative injury of the ileum and the remote organ lung. Peptides. Sep 2015;71:8-19. [CrossRef]
30. Zahra Eslamifar, Abbas Moridnia, Susan Sabbagh, Reza Ghaffaripour, Leila Jafaripour, Mahin Behzadifard, "Ameliorative Effects of Gallic Acid on Cisplatin-Induced Nephrotoxicity in Rat Variations of Biochemistry, Histopathology, and Gene Expression", BioMed Research International, vol. 2021, Article ID 2195238, 11 pages, 2021. [CrossRef]
31. Alibakhshi T, Khodayar MJ, Khorsandi L, Rashno M, Zeidooni L. Protective effects of zingerone on oxidative stress and inflammation in cisplatin-induced rat nephrotoxicity. Biomedicine & Pharmacotherapy 2018;105:225-32. [CrossRef]
32. Haghighi M, Nematbakhsh M, Talebi A, et al. The role of angiotensin II receptor 1 (AT1) blockade in cisplatin-induced nephrotoxicity in rats: gender-related differences. Ren Fail. 2012;34(8):1046-51. [CrossRef]
33. Salama RH. Matricaria chamomilla attenuates cisplatin nephrotoxicity. Saudi J Kidney Dis Transpl. Jul 2012;23(4):765-72. [CrossRef]
34. Şen L., Özdemir K. , Memi G., Ercan F., Yeğen B. , Yeğen C. The gastroprotective effect of obestatin on indomethacin-induced acute ulcer is mediated by a vagovagal mechanism. Physiology international, 2020. [CrossRef]
35. Koyuncuoğlu, T., Vızdıklar, C., Üren, D., Yılmaz, H., Yıldırım, Ç., Atal, S. S., ... & Yeğen, B. Ç. Obestatin improves oxidative brain damage and memory dysfunction in rats induced with an epileptic seizure. Peptides 90 (2017): 37-47.
36. Lauwers E, Landuyt B, Arckens L, Schoofs L, Luyten W. Obestatin does not activate orphan G proteincoupled receptor GPR39. Biochem Biophys Res Commun. Dec 8 2006;351(1):21-5. [CrossRef]
37. Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest. Sep 2002;110(6):835-42. [CrossRef]
38. Zhang Q, Dong XW, Xia JY, Xu KY, Xu ZR. Obestatin Plays Beneficial Role in Cardiomyocyte Injury Induced by Ischemia-Reperfusion In Vivo and In Vitro. Med Sci Monit. May 4 2017;23:2127-2136. [CrossRef]
39. Mirarab E, Hojati V, Vaezi G, Shiravi A, Khaksari M. Obestatin inhibits apoptosis and astrogliosis of hippocampal neurons following global cerebral ischemia reperfusion via antioxidant and antiinflammatory mechanisms. Iran J Basic Med Sci. Jun 2019;22(6):617-622. [CrossRef]
40. El-Gohary OA. Obestatin improves hepatic injury induced by ischemia/reperfusion in rats: Role of nitric oxide. Gen Physiol Biophys. Jan 2017;36(1):109-115. [CrossRef]
41. Dembinski A, Warzecha Z, Ceranowicz P, et al. Administration of obestatin accelerates the healing of chronic gastric ulcers in rats. Med Sci Monit. Aug 2011;17(8):BR196-200. [CrossRef]
42. Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC. Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease. Clin Exp Pharmacol Physiol. Jan 2010;37(1):125-31. [CrossRef]
43. Ozkok A, Edelstein CL. Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res Int. 2014;2014:967826. [CrossRef]
44. Sanchez-Gonzalez PD, Lopez-Hernandez FJ, Lopez-Novoa JM, Morales AI. An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity. Crit Rev Toxicol. Nov 2011;41(10):803-21. [CrossRef]
45. Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury: an increasing global concern. Lancet. Jul 13 2013;382(9887):170-9. [CrossRef]
46. Bonegio R, Lieberthal W. Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens. May 2002;11(3):301-8. [CrossRef]
47. Gabbiani C, Magherini F, Modesti A, Messori L. Proteomic and metallomic strategies for understanding the mode of action of anticancer metallodrugs. Anticancer Agents Med Chem. May 2010;10(4):324-37. [CrossRef]
48. Siskind LJ, Kolesnick RN, Colombini M. Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem. Jul 26 2002;277(30):26796-803. [CrossRef]
49. McSweeney, K.R.; Gadanec, L.K.; Qaradakhi, T.; Ali, B.A.; Zulli, A.; Apostolopoulos, V. Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations. Cancers 2021, 13, 1572. [CrossRef]
50. Singh G. A possible cellular mechanism of cisplatin-induced nephrotoxicity. Toxicology. 1989;58(1):71– 80. [CrossRef]
51. Dobyan D. C., Levi J., Jacobs C., Kosek J., Weiner M. W. Mechanism of cis-platinum nephrotoxicity: II. Morphologic observations. The Journal of Pharmacology and Experimental Therapeutics. 1980;213(3):551–556.
52. Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M, Fadillioglu E. Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin Chim Acta. 2004 Oct;348(1-2):27-34. doi: [CrossRef]

Details

Primary Language

English

Subjects

Clinical Pharmacy and Pharmacy Practice

Journal Section

Research Article

Authors

Zarife Özdemir Kumral ^*
0000-0002-9485-0174
Türkiye

Alisina Bulut ^* This is me
0000-0003-3849-3333
Türkiye

Bahadır Üzülmez ^* This is me
0000-0002-9506-4765
Türkiye

Mustafa Vezirhüyük ^*
0000-0003-4248-1431
Türkiye

Zafer Kök ^*
0000-0001-7458-9135
Türkiye

Naziye Özkan Yenal
0000-0003-3524-0672
Türkiye

Berrak Yegen
0000-0003-0791-0165
Türkiye

Mehmet Koç
0000-0002-1433-8403
Türkiye

Publication Date

June 28, 2025

Submission Date

July 28, 2022

Acceptance Date

August 21, 2022

Published in Issue

Year 2022 Volume: 26 Number: 5

IZ

https://izlik.org/JA59KM38HP

Cite

RIS / Bibtex

APA

Özdemir Kumral, Z., Bulut, A., Üzülmez, B., Vezirhüyük, M., Kök, Z., Özkan Yenal, N., Yegen, B., & Koç, M. (2025). The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury. Journal of Research in Pharmacy, 26(5), 1375-1385. https://izlik.org/JA59KM38HP

AMA

1.Özdemir Kumral Z, Bulut A, Üzülmez B, et al. The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury. J. Res. Pharm. 2025;26(5):1375-1385. https://izlik.org/JA59KM38HP

Chicago

Özdemir Kumral, Zarife, Alisina Bulut, Bahadır Üzülmez, et al. 2025. “The Potency of Obestatin in Improving Kidney Functions and Apoptosis in Rats With Cisplatin-Induced Acute Kidney Injury”. Journal of Research in Pharmacy 26 (5): 1375-85. https://izlik.org/JA59KM38HP.

EndNote

Özdemir Kumral Z, Bulut A, Üzülmez B, Vezirhüyük M, Kök Z, Özkan Yenal N, Yegen B, Koç M (June 1, 2025) The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury. Journal of Research in Pharmacy 26 5 1375–1385.

IEEE

[1]Z. Özdemir Kumral et al., “The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury”, J. Res. Pharm., vol. 26, no. 5, pp. 1375–1385, June 2025, [Online]. Available: https://izlik.org/JA59KM38HP

ISNAD

Özdemir Kumral, Zarife - Bulut, Alisina - Üzülmez, Bahadır - Vezirhüyük, Mustafa - Kök, Zafer - Özkan Yenal, Naziye - Yegen, Berrak - Koç, Mehmet. “The Potency of Obestatin in Improving Kidney Functions and Apoptosis in Rats With Cisplatin-Induced Acute Kidney Injury”. Journal of Research in Pharmacy 26/5 (June 1, 2025): 1375-1385. https://izlik.org/JA59KM38HP.

JAMA

1.Özdemir Kumral Z, Bulut A, Üzülmez B, Vezirhüyük M, Kök Z, Özkan Yenal N, Yegen B, Koç M. The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury. J. Res. Pharm. 2025;26:1375–1385.

MLA

Özdemir Kumral, Zarife, et al. “The Potency of Obestatin in Improving Kidney Functions and Apoptosis in Rats With Cisplatin-Induced Acute Kidney Injury”. Journal of Research in Pharmacy, vol. 26, no. 5, June 2025, pp. 1375-8, https://izlik.org/JA59KM38HP.

Vancouver

1.Zarife Özdemir Kumral, Alisina Bulut, Bahadır Üzülmez, Mustafa Vezirhüyük, Zafer Kök, Naziye Özkan Yenal, Berrak Yegen, Mehmet Koç. The potency of obestatin in improving kidney functions and apoptosis in rats with cisplatin-induced acute kidney injury. J. Res. Pharm. [Internet]. 2025 Jun. 1;26(5):1375-8. Available from: https://izlik.org/JA59KM38HP