Skip to main content
SpringerLink
Log in

Prophylactic effect of ethyl pyruvate on renal ischemia/reperfusion injury mediated through oxidative stress

  • Urology - Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

As oxidative stress (OXS) has been shown to play a primary role in renal ischemia/reperfusion injury (RIRI), we investigated whether antioxidant such as ethyl pyruvate (EPy) might effectively prevent RIRI. Possible prophylactic effects of EPy and mannitol (Mann), one of perioperative agents often used, were tested against harmful OXS in vitro.

Methods

Hydrogen peroxide (H2O2) was used to exert OXS on the renal proximal tubular MDCK cells. Severity of OXS and protective effects of EPy and Mann were assessed by lipid peroxidation assay and cell viability test, respectively. The cytotoxic mechanism of H2O2 was explored by examining the status of glycolysis, metabolic signaling pathways, cell cycle, and induction of apoptosis.

Results

Although H2O2 (500 µM) increased OXS by ~ 3.5 times of controls, EPy (1 mM) fully reduced it to the basal level. Cell viability declined to merely 10% by H2O2 was regained to > 90% with EPy. Hexokinase activity and ATP level also declined significantly by H2O2, but they sustained 80–90% with EPy. Additionally, H2O2 led to the modulations of metabolic signaling regulators, a G1 cell cycle arrest, and induction of apoptosis, which were yet prevented with EPy. Unlike EPy, Mann had virtually little effects.

Conclusions

OXS can indeed lead to the significant cell viability reduction through its adverse cellular effects, ultimately resulting in RIRI. However, EPy appears to prevent these effects and protect MDCK cells, while Mann does not. Thus, EPy could be a more effective prophylactic renoprotective agent (than Mann) against oxidative renal cell injury including RIRI.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Baliga R, Ueda N, Walker PD, Shah SV (1997) Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis 29:465–477

    Article  CAS  PubMed  Google Scholar 

  2. Diamond JR (1992) The role of reactive oxygen species in animal models of glomerular disease. Am J Kidney Dis 19:292–300

    Article  CAS  PubMed  Google Scholar 

  3. Andreoli SP, McAteer JA (1990) Reactive oxygen molecule-mediated injury in endothelial and renal tubular epithelial cells in vitro. Kidney Int 38:785–794

    Article  CAS  PubMed  Google Scholar 

  4. Versteilen AM, Di Maggio F, Leemreis JR et al (2004) Molecular mechanisms of acute renal failure following ischemia/reperfusion. Int J Artif Organs 27:1019–1029

    Article  CAS  PubMed  Google Scholar 

  5. Zacharias M, Conlon NP, Herbison GP et al (2013) Interventions for protecting renal function in the perioperative period. Cochrane Database Syst Rev 11:CD003590

    Google Scholar 

  6. Dorman HR, Sondheimer JH, Cadnapaphornchai P (1990) Mannitol-induced acute renal failure. Medicine (Baltimore) 69:153–159

    Article  CAS  Google Scholar 

  7. Cutler RG (1991) Antioxidants and aging. Am J Clin Nutr 53:373S–379S

    Article  CAS  PubMed  Google Scholar 

  8. Reade MC, Fink MP (2005) Bench-to-bedside review: amelioration of acute renal impairment using ethyl pyruvate. Crit Care 9:556–560

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fink MP (2007) Ethyl pyruvate: a novel anti-inflammatory agent. J Intern Med 261:349–362

    Article  CAS  PubMed  Google Scholar 

  10. Cruz RJ Jr, Harada T, Sasatomi E, Fink MP (2011) Effects of ethyl pyruvate and other α-keto carboxylic acid derivatives in a rat model of multivisceral ischemia and reperfusion. J Surg Res 165:151–157

    Article  CAS  PubMed  Google Scholar 

  11. Sims CA, Wattanasirichaigoon S, Menconi MJ et al (2001) Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. Crit Care Med 29:1513–1518

    Article  CAS  PubMed  Google Scholar 

  12. Uchiyama T, Delude RL, Fink MP (2003) Dose-dependent effects of ethyl pyruvate in mice subjected to mesenteric ischemia and reperfusion. Intensive Care Med 29:2050–2058

    Article  PubMed  Google Scholar 

  13. Tsung A, Kaizu T, Nakao A et al (2005) Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. Transplantation 79:196–204

    Article  CAS  PubMed  Google Scholar 

  14. Dargel R (1992) Lipid peroxidation: a common pathogenetic mechanism? Exp Toxic Pathol 44:169–181

    Article  CAS  Google Scholar 

  15. Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25:4633–4646

    Article  CAS  PubMed  Google Scholar 

  16. Simons AL, Mattson DM, Dornfeld K, Spitz DR (2009) Glucose deprivation-induced metabolic oxidative stress and cancer therapy. J Cancer Res Ther 5:S2–S6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Miccoli L, Oudard S, Sureau F et al (1996) Intracellular pH governs the subcellular distribution of hexokinase in a glioma cell line. Biochem J 313:957–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cheong JH, Park ES, Liang J et al (2011) Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther 10:2350–2362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Priebe A, Tan L, Wahl H et al (2011) Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells. Gynecol Oncol 122:389–395

    Article  CAS  PubMed  Google Scholar 

  20. Lee YK, Park OJ (2010) Regulation of mutual inhibitory activities between AMPK and Akt with quercetin in MCF-7 breast cancer cells. Oncol Rep 24:1493–1497

    CAS  PubMed  Google Scholar 

  21. Bolster DR, Crozier SJ, Kimball SR, Jefferson LS (2002) AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 277:23977–23980

    Article  CAS  PubMed  Google Scholar 

  22. Loar P, Wahl H, Kshirsagar M et al (2010) Inhibition of glycolysis enhances cisplatin-induced apoptosis in ovarian cancer cells. Am J Obstet Gynecol 202:371.e1–371.e8

    Article  CAS  Google Scholar 

  23. Sherr CJ (2000) The Pezcoller lecture: cancer cell cycles revised. Cancer Res 60:3689–3695

    CAS  PubMed  Google Scholar 

  24. Yip KW, Reed JC (2008) Bcl-2 family proteins and cancer. Oncogene 27:6398–6406

    Article  CAS  PubMed  Google Scholar 

  25. Jun JH, Song JW, Shin EJ, Kwak YL, Choi N, Shim JK (2018) Ethyl pyruvate is renoprotective against ischemia-reperfusion injury under hyperglycemia. J Thorac Cardiovasc Surg 155:1650–1658

    Article  CAS  PubMed  Google Scholar 

  26. Yang R, Gallo DJ, Baust JJ et al (2002) Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 283:G212–G221

    Article  CAS  PubMed  Google Scholar 

  27. Kelle I, Akkoc H, Tunik S, Nergiz Y, Erdinc M, Erdinc L (2014) Protective effects of ethyl pyruvate in cisplatin-induced nephrotoxicity. Biotechnol Biotechnol Equip 28:674–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Matsushima H, Yonemura K, Ohishi K, Hishida A (1998) The role of oxygen free radicals in cisplatin-induced acute renal failure in rats. J Lab Clin Med 131:518–526

    Article  CAS  Google Scholar 

  29. Kuhajda FP (2008) AMP-activated protein kinase and human cancer: cancer metabolism revisited. Int J Obes (Lond) 32:S36–S41

    Article  CAS  Google Scholar 

  30. MacFarlane M, Robinson GL, Cain K (2012) Glucose—a sweet way to die: metabolic switching modulates tumor cell death. Cell Cycle 11:3919–3925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bennett-Guerrero E, Swaminathan M, Grigore AM et al (2009) A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 23:324–329

    Article  CAS  PubMed  Google Scholar 

  32. Yu YM, Kim JB, Lee KW, Kim SY, Han PL, Lee JK (2005) Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window. Stroke 36:2238–2243

    Article  CAS  Google Scholar 

  33. Yang R, Zhu S, Tonnessen TI (2016) Ethyl pyruvate is a novel anti-inflammatory agent to treat multiple inflammatory organ injuries. J Inflamm (Lond) 13:37.e

    Article  CAS  Google Scholar 

  34. Yang R, Uchiyama T, Alber SM et al (2004) Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis. Crit Care Med 32:1453–1459

    Article  CAS  PubMed  Google Scholar 

  35. Ulloa L, Ochani M, Yang H et al (2002) Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 99:12351–12356

    Article  CAS  Google Scholar 

  36. Jung SM, Lee J, Baek SY et al (2017) Ethyl pyruvate ameliorates inflammatory arthritis in mice. Int Immunopharmacol 52:333–341

    Article  CAS  PubMed  Google Scholar 

  37. Cook VL, Holcombe SJ, Gandy JC, Corl CM, Sordillo LM (2011) Ethyl pyruvate decreases proinflammatory gene expression in lipopolysaccharide-stimulated equine monocytes. Vet Immunol Immunopathol 141:92–99

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank “mamjp.org” (Tokyo, Japan) for generous financial support in this study.

Author information

Authors and Affiliations

  1. Department of Urology, New York Medical College, Valhalla, NY, 10595, USA

    Jonathan Bloom, Neel Patel, Jonathan Wagmaister, Muhammad Choudhury, Majid Eshghi & Sensuke Konno

  2. Department of Urology, New York Medical College, BSB, Room A03, Valhalla, NY, 10595, USA

    Sensuke Konno

Authors
  1. Jonathan Bloom
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neel Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan Wagmaister
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammad Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Majid Eshghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sensuke Konno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sensuke Konno.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bloom, J., Patel, N., Wagmaister, J. et al. Prophylactic effect of ethyl pyruvate on renal ischemia/reperfusion injury mediated through oxidative stress. Int Urol Nephrol 51, 85–92 (2019). https://doi.org/10.1007/s11255-018-2020-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-018-2020-9

Keywords

Search

Navigation