Ukr.Biochem.J. 2021; Volume 93, Issue 1, Jan-Feb, pp. 51-58


Leptin and curcumin affect renal ischemia-reperfusion injury via modulation of P65 and Bax genes expression

M. M. Ragy1, M. M. Ramzy2*

1Physiology Department, Faculty of Medicine, Minia University, Misr-Aswan Road, Egypt;
2Biochemistry Department, Faculty of Medicine, Minia University, Misr-Aswan Road, Egypt;

Received: 01 June 2020; Accepted: 17 December 2020

Ischemia and reperfusion are natural steps during kidney transplantation, and ischemia-reperfusion injury is a critical condition in which physicians must preserve organ function and control cell damage. As leptin is thought to play an important role in the regulation of the immune system and inflammation and curcumin is a potent anti-fibrotic agent, both agents are promising to have therapeutic impact on renal damage. The present study was designed to evaluate the effects of leptin and curcumin on renal ischemia-reperfusion injury. Forty adult male albino rats were divided into four groups: control; ischemia-reperfusion (I/R), leptin-treated (leptin was injected intraperitoneally at a dose 100 μg/kg for 3 days prior to ischemia) and curcumin-treated (curcumin was given orally at a dose of 50 mg/kg/day for 5 days before ischemia). All rats were sacrificed 24 hours after reperfusion. Serum urea and creatinine, renal malondialdehyde and total antioxidant capacity were measured. Renal TNF-α was assayed by ELISA and P65 and Bax mRNA expression were determined using RT-PCR. Our results demonstrated a significant increase in P65 and Bax mRNA expression after renal ischemia-reperfusion injury compared to control group. Both leptin and curcumin prevented oxidative damage of the renal tissues as they lowered MDA and nitric oxide levels, increased antioxidant capacity and decreased TNF-α level. It was shown that protective leptin and curcumin effect against kidney IR-induced oxidative injury was associated with a down-regulation of P65 and Bax expression. These results show that ischemia-reperfusion leads to renal damage and also they reveal that both leptin and curcumin have protective implications which may be promising agents for avoiding various adverse effects.

Keywords: , , , , ,


  1. Jung HS, Joo JD, Kim DW, In JH, Roh M, Jeong JT, Noh SJ, Choi JW. Effect of milrinone on the inflammatory response and NF-kB activation in renal ischemia-reperfusion injury in mice. Korean J Anesthesiol. 2014;66(2):136-142. PubMed, PubMedCentral, CrossRef
  2. Zhang WZ, Li R, Liu S, Zhang JD, Ning XF, Cai SL. Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits. Biomed Res Int. 2016;2016:9349437. PubMed, PubMedCentral, CrossRef
  3. Ling Hou L, Chen G, Feng B, Zhang XS, Zheng XF, Xiang Y, Zhao GY, Min WP. Small interfering RNA targeting TNF-α gene significantly attenuates renal ischemia-reperfusion injury in mice. J Huazhong Univ Sci Technolog Med Sci. 2016;36(5):634-638. PubMed, CrossRef
  4. Zhang H, Sun SC. NF-κB in inflammation and renal diseases. Cell Biosci. 2015;5:63. PubMed, PubMedCentral, CrossRef
  5. Kumar D, Singla SK, Puri V, Puri S. The restrained expression of NF-kB in renal tissue ameliorates folic acid induced acute kidney injury in mice. PLoS One. 2015;10(1):e115947. PubMed, PubMedCentral, CrossRef
  6. Sanz AB, Sanchez-Niño MD, Ramos AM, Moreno JA, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A. NF-kappaB in renal inflammation. J Am Soc Nephrol. 2010;21(8):1254-1262. PubMed, CrossRef
  7. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609-619. PubMed, CrossRef
  8. Martin SJ, Henry CM, Cullen SP. A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol Cell. 2012;46(4):387-397.
    PubMed, CrossRef
  9. Poljaroen J, Tinikul Y, Tinikul R, Anurucpreeda P, Sobhon P. Leptin-like immunoreactivity in the central nervous system, digestive organs, and gonads of the giant freshwater prawn, Macrobrachium rosenbergii. Acta Histochem. 2017;119(5):569-581. PubMed, CrossRef
  10. Caszo B, Muslim A, Awang Z, Omar E, Ibrahim E, Singh H. The effects of leptin administration on renal function in spontaneously hypertensive rats. Asian J Pharm Clin Res. 2017;10(1):108-110. CrossRef
  11. Yan GT, Xue H, Lin J, Hao XH, Zhang K, Wang LH. Leptin protects sepsis-induced renal injury and research for its mechanism. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2006;18(11):665-667. PubMed
  12. Adahoun MA, Al-Akhras MH, Jaafar MS, Bououdina M. Enhanced anti-cancer and antimicrobial activities of curcumin nanoparticles. Artif Cells Nanomed Biotechnol. 2017;45(1):98-107.  PubMed, CrossRef
  13. Zhang J, Tang L, Li GS, Wang J. The anti-inflammatory effects of curcumin on renal ischemia-reperfusion injury in rats. Ren Fail. 2018;40(1):680-686. PubMed, PubMedCentral, CrossRef
  14. Sagiroglu T, Torun N, Yagci M, Yalta T, Sagiroglu G, Oguz S. Effects of apelin and leptin on renal functions following renal ischemia/reperfusion: An experimental study. Exp Ther Med. 2012;3(5):908-914. PubMed, PubMedCentral, CrossRef
  15. Erturk N, Elbe H, Dogan Z, Aktas S, Demirbilek S, Ozturk F. Curcumin prevents renal oxidative stress and tissue damage induced by renal ischemia/reperfusion in rats. Int Surgery J. 2018;5(10):3192-3197. CrossRef
  16. Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY, Li CJ. Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cell Physiol Biochem. 2018;46(4):1650-1667. PubMed, CrossRef
  17. Markó L, Vigolo E, Hinze C, Park JK, Roël G, Balogh A, Choi M, Wübken A, Cording J, Blasig IE, Luft FC, Scheidereit C, Schmidt-Ott KM, Schmidt-Ullrich R, Müller DN. Tubular Epithelial NF-κB Activity Regulates Ischemic AKI. J Am Soc Nephrol. 2016;27(9):2658-2669. PubMed, PubMedCentral, CrossRef
  18. Rabb H, Griffin MD, McKay DB, Swaminathan S, Pickkers P, Rosner MH, Kellum JA, Ronco C. Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps. J Am Soc Nephrol. 2016;27(2):371-379. PubMed, PubMedCentral, CrossRef
  19. Ornellas FM, Ornellas DS, Martini SV, Castiglione RC, Ventura GM, Rocco PR, Gutfilen B, de Souza SA, Takiya CM, Morales MM. Bone Marrow-Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules. Cell Physiol Biochem. 2017;41(5):1736-1752. PubMed, CrossRef
  20. Hentia C, Rizzato A, Camporesi E, Yang Z, Muntean DM, Săndesc D, Bosco G. An overview of protective strategies against ischemia/reperfusion injury: The role of hyperbaric oxygen preconditioning. Brain Behav. 2018;8(5):e00959. PubMed, PubMedCentral, CrossRef
  21. Shu Y, Yang Y, Zhao Y, Ma L, Fu P, Wei T, Zhang L. Melittin Inducing the Apoptosis of Renal Tubule Epithelial Cells through Upregulation of Bax/Bcl-2 Expression and Activation of TNF- α Signaling Pathway. Biomed Res Int. 2019;2019:9450368. PubMed, PubMedCentral, CrossRef
  22. Saral S, Dokumacioglu E, Mercantepe T, Atak M, Cinar S, Saral O, Yildiz L, Iskender H , Tumkaya L. The effect of white tea on serum TNF-α/NF-κB and immunohistochemical parameters in cisplatin-related renal dysfunction in female rats. Biomed Pharmacother. 2019;112:108604. PubMed, CrossRef
  23. Xiao K, Liu C, Tu Z, Xu Q, Chen S, Zhang Y, Wang X, Zhang J, Hu CAA, Liu Y. Activation of the NF- κ B and MAPK Signaling Pathways Contributes to the Inflammatory Responses, but Not Cell Injury, in IPEC-1 Cells Challenged with Hydrogen Peroxide. Oxid Med Cell Longev. 2020;2020:5803639. PubMed, PubMedCentral, CrossRef
  24. Sarsu SB, Ozokutan BH, Tarakcioglu M, Sarı I, Bağcı C. Effects of Leptin on Intestinal Ischemia-Reperfusion Injury. Indian J Surg. 2015;77(Suppl 2):351-355. PubMed, PubMedCentral, CrossRef
  25. Zhang WF, Jin YC, Li XM, Yang Z, Wang D, Cui JJ. Protective effects of leptin against cerebral ischemia/reperfusion injury. Exp Ther Med. 2019;17(5):3282-3290. PubMed, PubMedCentral, CrossRef
  26. Lopez-Rodriguez AB, Mela V, Acaz-Fonseca E, Garcia-Segura LM, Viveros MP. CB2 cannabinoid receptor is involved in the anti-inflammatory effects of leptin in a model of traumatic brain injury. Exp Neurol. 2016;279:274-282. PubMed, CrossRef
  27. Brown JE, Dunmore SJ. Leptin decreases apoptosis and alters BCL-2 : Bax ratio in clonal rodent pancreatic beta-cells. Diabetes Metab Res Rev. 2007;23(6):497-502. PubMed, CrossRef
  28. Valerio A, Dossena M, Bertolotti P, Boroni F, Sarnico I, Faraco G, Chiarugi A, Frontini A, Giordano A, Liou HC, De Simoni MG, Spano P, Carruba MO, Pizzi M, Nisoli E. Leptin is induced in the ischemic cerebral cortex and exerts neuroprotection through NF-kappaB/c-Rel-dependent transcription. Stroke. 2009;40(2):610-617. PubMed, CrossRef
  29. Toro AR, Maymó JL, Ibarbalz FM, Pérez-Pérez A, Maskin B, Faletti AG, Sánchez-Margalet V, Varone CL. Leptin is an anti-apoptotic effector in placental cells involving p53 downregulation. PLoS One. 2014;9(6):e99187. PubMed, PubMedCentral, CrossRef
  30. Shen S, Zhou J, Meng S, Wu J, Ma J, Zhu C, Deng G, Liu D. The protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax. Exp Ther Med. 2017;14(5):4077-4082. PubMed, PubMedCentral, CrossRef
  31. Prabhakar SS.  Effects of curcumin in experimental diabetic nephropathy. J Investig Med. 2017;65(1):1-6. PubMed, CrossRef
  32. Abarikwu SO, Durojaiye M, Alabi A, Asonye B, Akiri O. Curcumin protects against gallic acid-induced oxidative stress, suppression of glutathione antioxidant defenses, hepatic and renal damage in rats. Ren Fail. 2016;38(2):321-329.  PubMed, CrossRef
  33. Aparicio-Trejo OE, Tapia E, Molina-Jijón E, Medina-Campos ON, Macías-Ruvalcaba NA, León-Contrerasv, Hernández-Pando R, García-Arroyo FE, Cristóbal M, Sánchez-Lozada LG, Pedraza-Chaverri J. Curcumin prevents mitochondrial dynamics disturbances in early 5/6 nephrectomy: Relation to oxidative stress and mitochondrial bioenergetics. Biofactors. 2017;43(2):293-310. PubMed, CrossRef
  34. He L, Peng X, Zhu J, Liu G, Chen X, Tang C, Liu H, Liu F, Peng Y. Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats. Can J Physiol Pharmacol. 2015;93(4):275-282. PubMed, CrossRef
  35. Soliman MM, Baiomy AA, Yassin MH.Molecular and Histopathological Study on the Ameliorative Effects of Curcumin Against Lead Acetate-Induced Hepatotoxicity and Nephrototoxicity in Wistar Rats. Biol Trace Elem Res. 2015;167(1):91-102. PubMed, CrossRef
  36. Topcu-Tarladacalisir Y, Sapmaz-Metin M, Karaca T. Curcumin counteracts cisplatin-induced nephrotoxicity by preventing renal tubular cell apoptosis. Ren Fail. 2016;38(10):1741-1748. PubMed, CrossRef
  37. Jacob A, Chaves L, Eadon MT, Chang A, Quigg RJ, Alexander JJ. Curcumin alleviates immune-complex-mediated glomerulonephritis in factor-H-deficient mice.  Immunology. 2013;139(3):328-337. PubMed, PubMedCentral, CrossRef
  38. Chiu J, Khan ZA, Farhangkhoee H, Chakrabarti S. Curcumin prevents diabetes-associated abnormalities in the kidneys by inhibiting p300 and nuclear factor-kappaB. Nutrition. 2009;25(9):964-972. PubMed, CrossRef
  39. Sharma S, Kulkarni SK, Chopra K. Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol. 2006;33(10):940-945. PubMed, CrossRef
  40. Tang M, Larson-Meyer DE, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. Am J Clin Nutr. 2008;87(5):1262-1267. PubMed, CrossRef
  41. Ghodasara J, Pawar A, Deshmukh C, Kuchekar B. Inhibitory effect of rutin and curcumin on experimentally-induced calcium oxalate urolithiasis in rats. Pharmacognosy Res. 2010;2(6):388-392. PubMed, PubMedCentral, CrossRef, CrossRef
  42. Buhrmann C, Mobasheri A, Busch F, Aldinger C, Stahlmann R, Montaseri A, Shakibaei M. Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 2011;286(32):28556-28566. PubMed, PubMedCentral, CrossRef
  43. Loganes C, Lega S, Bramuzzo M, Brumatti LV, Piscianz E, Valencic E, Tommasini A, Marcuzzi A. Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage. Nutrients. 2017;9(6):578. PubMed, PubMedCentral, CrossRef
  44. Yang D, Li Y, Zhao D. Curcumin induces apoptotic cell death in human pancreatic cancer cells via the miR-340/XIAP signaling pathway. Oncol Lett. 2017;14(2):1811-1816. PubMed, PubMedCentral, CrossRef
  45. Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TWB. Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation. Am J Physiol Renal Physiol. 2009;296(5):F1146-F1157. PubMed, CrossRef
  46. Trujillo J, Chirino YI, Molina-Jijón E, Andérica-Romero AC, Tapia E, Pedraza-Chaverrí J. Renoprotective effect of the antioxidant curcumin: Recent findings. Redox Biol. 2013;1(1):448-456. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.