Skip to main content

Advertisement

SpringerLink
Log in

The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Oxidative stress and inflammation play a key role in the development of hepatic ischemia reperfusion (HIR)-induced injury. Nuclear factor-erythroid 2-related factor-2 (Nrf-2) is a main regulator of numerous genes, encoding cytoprotective molecules including heme oxygenase-1 (HO-1). Sitagliptin (Sit) is an incretin enhancer acting via inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme. This study was undertaken to investigate the ability of Sit to prevent the hepatic pathological changes of HIR induced injury and to modify Nrf-2 and its target HO-1.

Methods

Pringle’s maneuver was used to induce total HIR in adult male rats that were randomly assigned into 4 groups. Groupl (sham-operated control), Group 2 (sham-operated + Sit-control group), Group 3 (HIR non-treated), and Group 4 (HIR+Sit). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities together with hepatic contents of malondialdhyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) and superoxide dismutase (SOD) activity were evaluated. Hepatic tissue mRNA of Nrf-2 and protein content of HO-1 along with histopathological examination and scoring of hepatic injury were performed.

Results

Sit caused a significant reduction in ALT and AST activities together with attenuation of HIR-induced histopathological liver injury. Effect of Sit was associated with decreased hepatic level of MDA and NO with increased GSH level and SOD activity. Non-treated rats with HIR showed an increase in Nrf-2 mRNA expression and HO-1 content in hepatic tissue which was further increased by Sit treatment.

Conclusions

These results indicate that hepatoprotective activity of Sit against HIR is attributed at least in part to modulation of Nrf-2/HO-1 signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Osman AS, Osman AH, Kamel MM. Study of the protective effect of ischemic and pharmacological preconditioning on hepatic ischemic reperfusion injury induced in rats. JGH Open 2017;1(3):105–11.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bektas S, Karakaya K, Can M, Bahadir B, Guven B, Erdogan N, et al. The effects of tadalafil and pentoxifylline on apoptosis and nitric oxide synthase in liver ischemia/reperfusion injury. Kaohsiung J Med Sci 2016;32(7):339–47.

    Article  PubMed  Google Scholar 

  3. Atef Y, El-Fayoumi HM, Abdel-Mottaleb Y, Mahmoud MF. Quercetin and tin protoporphyrin attenuate hepatic ischemia reperfusion injury: role of HO-1. Naunyn Schmiedebergs Arch Pharmacol 2017;390(9):871–81.

    Article  CAS  PubMed  Google Scholar 

  4. Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, et al. Nrf2, a multi-organ protector? FASEB J 2005;19(9):1061–6.

    Article  PubMed  Google Scholar 

  5. Masuda Y, Vaziri ND, Takasu C, Li S, Robles L, Pham C, et al. Salutary effect of pre-treatment with an Nrf2 inducer on ischemia reperfusion injury in the rat liver. Gastroenterol Hepatol (Que) 2014;1(1):1–7.

    PubMed  Google Scholar 

  6. Ke B, Shen XD, Zhang Y, Ji H, Gao F, Yue S, et al. KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. J Hepatol 2013;59(6):1200–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nishikawa Y, Stepp DW, Merkus D, Jones D, Chilian WM. In vivo role of heme oxygenase in ischemic coronary vasodilation. Am J Physiol Heart Circ Physiol 2004;286(6):H2296–304.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang GY, Wang DD, Cao Z, Wei T, Liu CX, Wei QL. Sitagliptin ameliorates high glucose-induced cell proliferation and expression of the extracellular matrix in glomerular mesangial cells. Exp Ther Med 2017;14(4):3862–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 2007;30 (6):1335–43.

    Article  CAS  PubMed  Google Scholar 

  10. Picatoste B, Ramirez E, Caro-Vadillo A, Iborra C, Ares-Carrasco S, Egido J, et al. Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms. PLoS One 2013;8(10)e78330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Geddawy A, Hussian M, Kamel MY, Kamal R, Ibrahim MA. Effects of Liraglutide and vitamin e in fructose-induced metabolic syndrome in rats. Pharmacology 2017;99(1-2):48–56.

    Article  CAS  PubMed  Google Scholar 

  12. Ibrahim MA, Geddawy A, Abdel-Wahab S. Sitagliptin prevents isoproterenol- induced myocardial infarction in rats by modulating nitric oxide synthase enzymes. Eur J Pharmacol 2018;829:63–9.

    Article  CAS  PubMed  Google Scholar 

  13. Trocha M, Nowak B, Merwid-Lad A, Szuba A, Dziegiel P, Piesniewska M, et al. The impact of sitagliptin, inhibitor of dipeptidyl peptidase-4 (DPP-4), on the ADMA-DDAH-NO pathway in ischemic and reperfused rat livers. Adv Clin Exp Med 2018;27(11):1483–90.

    Article  PubMed  Google Scholar 

  14. Tang ST, Su H, Zhang Q, Tang HQ, Wang CJ, Zhou Q, et al. Sitagliptin inhibits endothelin-1 expression in the aortic endothelium of rats with streptozotocin- induced diabetes by suppressing the nuclear factor-kappaB/IkappaBalpha system through the activation of AMP-activated protein kinase. Int J Mol Med 2016;37(6):1558–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abdel-Gaber SA, Ibrahim MA, Amin EF, Ibrahim SA, Mohammed RK, Abdelrahman AM. Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats. Life Sci 2015;134:42–8.

    Article  CAS  PubMed  Google Scholar 

  16. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978;52:302–10.

    Article  CAS  PubMed  Google Scholar 

  17. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 1974;47(3):469–74.

    Article  CAS  PubMed  Google Scholar 

  18. Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 1979;582(1):67–78.

    Article  CAS  PubMed  Google Scholar 

  19. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982;126(1):131–8.

    Article  CAS  PubMed  Google Scholar 

  20. VanGuilder HD, Vrana KE, Freeman WM. Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques 2008;44(5):619–26.

    Article  Google Scholar 

  21. Wei Y, Chen P, de Bruyn M, Zhang W, Bremer E, Helfrich W Carbon monoxide-releasing molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats. BMC Gastroenterol 2010; 10:42.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guan LY, Fu PY, Li PD, Li ZN, Liu HY, Xin MG, et al. Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide. World J Gastrointest Surg 2014;6(7):122–8.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cannistra M, Ruggiero M, Zullo A, Gallelli G, Serafini S, Maria M, et al. Hepatic ischemia reperfusion injury: a systematic review of literature and the role of current drugs and biomarkers. Int J Surg 2016;33(Suppl. 1):S57–70.

    Article  PubMed  Google Scholar 

  24. Ibrahim MA, Abdel-Gaber SA, Amin EF, Ibrahim SA, Mohammed RK, Abdelrahman AM. Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury. Eur J Pharmacol 2014;741:64–73.

    Article  CAS  PubMed  Google Scholar 

  25. Mard SA, Akbari G, Dianat M, Mansouri E. The effect of zinc sulfate on miR-122, miR-34a, atioxidants, biochemical and histopathological parameters following hepatic Ischemia/Reperfusion injury in rats. Biol Trace Elem Res 2019; 188 (2):434–40.

    Article  CAS  PubMed  Google Scholar 

  26. Huang XL, He Y, Ji LL, Wang KY, Wang YL, Chen DF, et al. Hepatoprotective potential of isoquercitrin against type 2 diabetes-induced hepatic injury in rats. Oncotarget 2017;8(60):101545–59.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sokar SS, El-Sayad ME, Ghoneim ME, Shebl AM. Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats. Biomed Pharmacother 2017;89:98–107.

    Article  CAS  PubMed  Google Scholar 

  28. Cutrin JC, Llesuy S, Boveris A. Primary role of Kupffer cell-hepatocyte communication in the expression of oxidative stress in the post-ischaemic liver. Cell Biochem Funct 1998;16(1):65–72.

    Article  CAS  PubMed  Google Scholar 

  29. Siriussawakul A, Zaky A, Lang JD. Role of nitric oxide in hepatic ischemia-reperfusion injury. World J Gastroenterol 2010;16(48):6079–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Abdel-Gaber SA, Mohammed RK Refaie MMM. Mechanism mediating the protective effect of diacerein in ischemia-reperfusion-induced testicular injury in rats. Life Sci 2018;209:57–62.

    Article  CAS  PubMed  Google Scholar 

  31. El-Sheikh AA, Morsy MA, Hamouda AH. Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats. Pharmacogn Mag 2016;12(Suppl. 1):S76–81.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology 2000;7 (3):153–63.

    Article  CAS  PubMed  Google Scholar 

  33. Civantos E, Bosch E, Ramirez E, Zhenyukh O, Egido J, Lorenzo O, et al. Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-l/Nrf2 antioxidant pathway. Diabetes Metab Syndr Obes 2017;10:207–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu L, Liu J, Tian XY, Wong WT, Lau CW, Xu A, et al. Uncoupling protein-2 mediates DPP-4 inhibitor-induced restoration of endothelial function in hypertension through reducing oxidative stress. Antioxid Redox Signal 2014;21(11):1571–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS. Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity. PLoS One 2017;12(3)e0174295.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chen M, Jiang L, Li Y, Bai G, Zhao J, Zhang M, et al. Hydrogen protects against liver injury during C02 pneumoperitoneum in rats. Oncotarget 2017;9(2):2631–45.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 2010;299(1):H18–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee D, Kook SH, Ji H, Lee SA, Choi KC, Lee KY, et al. N-acetyl cysteine inhibits H202-mediated reduction in the mineralization of MC3T3-E1 cells by down-regulating Nrf2/HO-1 pathway. BMB Rep 2015;48(11):636–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Morse D, Lin L, Choi AMK, Ryter SW Heme oxygenase-1, a critical arbitrator of cell death pathways in Jung injury and disease. Free Radic Biol Med 2009;47(1):1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Leffler CW, Nasjletti A, Yu C, Johnson RA, Fedinec AL, Walker N. Carbon monoxide and cerebral microvascular tone in newborn pigs. Am J Physiol 1999;276(5):H1641–6.

    CAS  PubMed  Google Scholar 

  41. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 2003;24(8):449–55.

    Article  CAS  PubMed  Google Scholar 

  42. Osburn WO, Wakabayashi N, Misra V, Nilles T, Biswal S, Trush MA, et al. Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Arch Biochem Biophys 2006;454(1):7–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kudoh K, Uchinami H, Yoshioka M, Seki E, Yamamoto Y Nrf2 activation protects the liver from ischemia/reperfusion injury in mice. Ann Surg 2014;260(1):118–27.

    Article  PubMed  Google Scholar 

  44. Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, et al. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 2008;104(1):218–27.

    Article  CAS  PubMed  Google Scholar 

  45. Chen J, Liu H, Zhang X. [Protective effects of rosiglitazone on hepatic ischemia reperfusion injury in rats]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018;43 (7):732–7.

    PubMed  Google Scholar 

  46. Shimada S, Fukai M, Wakayama K, Ishikawa T, Kobayashi N, Kimura T, et al. Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. Surg Today 2015;45(7):892–903.

    Article  CAS  PubMed  Google Scholar 

  47. Patel A, Zhang S, Shrestha AK, Maturu P, Moorthy B, Shivanna B. Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway. Toxicol Appl Pharmacol 2016;311:26–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang CH, Zhu N. Protective role of sitagliptin against oxidative stress in a kainic acid-induced status epilepticus in rats models via Nrf2/HO-1 pathway. Drug Dev Res 2019.

    Google Scholar 

  49. Wang J, Hu L, Chen Y, Fu T, Jiang T, Jiang A, et al. Sitagliptin improves renal function in diabetic nephropathy in male Sprague Dawley rats through upregulating heme oxygenase-1 expression. Endocrine 2019;63(1):70–8.

    Article  CAS  PubMed  Google Scholar 

  50. Chang MW, Chen CH, Chen YC, Wu YC, Zhen YY, Leu S, et al. Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors. Acta Pharmacol Sin 2015;36(1):119–30.

    Article  CAS  PubMed  Google Scholar 

  51. Chua S, Lee FY, Tsai TH, Sheu JJ, Leu S, Sun CK et al. Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats. J Transl Med 2014;12:357.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Turkseven S, Kruger A, Mingone CJ, Kaminski P, Inaba M, Rodella LF, et al. Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. Am J Physiol Heart Circ Physiol 2005;289(2):H701–7.

    Article  CAS  PubMed  Google Scholar 

  53. Gupta NA, Kolachala VL, Jiang R, Abramowsky C, Romero R, Fifadara N, et al. The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis. Am J Pathol 2012;181(5):1693–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt

    Seham A. Abdel-Gaber & Ayman Geddawy

  2. Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia

    Ayman Geddawy

  3. Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt

    Rabab A. Moussa

Authors
  1. Seham A. Abdel-Gaber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayman Geddawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rabab A. Moussa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayman Geddawy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdel-Gaber, S.A., Geddawy, A. & Moussa, R.A. The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway. Pharmacol. Rep 71, 1044–1049 (2019). https://doi.org/10.1016/j.pharep.2019.06.006

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2019.06.006

Keywords

Search

Navigation