The Role of Glyoxalase System in Renal Hypoxia

  • Reiko Inagi
  • Takanori Kumagai
  • Toshiro Fujita
  • Masaomi Nangaku
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 662)

Abstract

Methylglyoxal (MG), a highly reactive α-oxoaldehyde generated by oxidation of carbohydrate and glycolysis, binds to proteins and forms advanced glycation end products (AGE). MG and MG adducts have been implicated in oxidative stress-related diseases, therefore, MG detoxifying system such as the glyoxalase system (glyoxalase I) also contributes to progression of these diseases. Recent papers have emphasized the pathophysiological effects of MG and the glyoxalase system in acute hypoxic injury, which is associated with acute oxidative stress. We investigated the kinetics of MG level and glyoxalase I activity in renal acute hypoxic injury induced by ischemia-reperfusion (I/R). I/R induced tubulointerstitial injury and the histological changes were associated with a significant decrease in renal glyoxalase I activity and an increase in MG level in the damaged tubular cells. Of note, rats over expressing human glyoxalase I showed amelioration of I/R-induced histological and functional damages and it was associated with a decrease in MG level in the lesion resulting in reduction of oxidative stress and tubular cell apoptosis. In conclusion, glyoxalase I has renoprotective effects in renal hypoxia such as I/R injury via a reduction in cytotoxic MG level in tubular cells.

References

  1. 1.
    Nangaku M (2006) Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 17:17–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Matsumoto M, Makino Y, Tanaka T et al. (2003) Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J Am Soc Nephrol 14:1825–1832.PubMedCrossRefGoogle Scholar
  3. 3.
    Ohtomo S, Nangaku M, Izuhara Y et al. (2008) Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model. Nephrol Dial Transplant 23:1166–1172.PubMedCrossRefGoogle Scholar
  4. 4.
    Kojima I, Tanaka T, Inagi R et al. (2007) Protective role of hypoxia-inducible factor-2alpha against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 18:1218–1226.PubMedCrossRefGoogle Scholar
  5. 5.
    Makino Y, Cao R, Svensson K et al. (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414:550–554.PubMedCrossRefGoogle Scholar
  6. 6.
    Biswas S, Ray M, Misra S et al. (1997) Selective inhibition of mitochondrial respiration and glycolysis in human leukaemic leucocytes by methylglyoxal. Biochem J 323:343–348.PubMedGoogle Scholar
  7. 7.
    de Arriba SG, Stuchbury G, Yarin J et al. (2007) Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells. Neurobiol Aging 28:1044–1050.PubMedCrossRefGoogle Scholar
  8. 8.
    Halder J, Ray M, Ray S (1993) Inhibition of glycolysis and mitochondrial respiration of Ehrlich ascites carcinoma cells by methylglyoxal. Int J Can-cer 54:443–449.Google Scholar
  9. 9.
    Chan WH, Wu HJ, Shiao NH (2007) Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. J Cell Biochem 100:1056–1069.PubMedCrossRefGoogle Scholar
  10. 10.
    Godbout JP, Pesavento J, Hartman ME et al. (2002) Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase C delta. J Biol Chem 277:2554–2561.PubMedCrossRefGoogle Scholar
  11. 11.
    Chan WH, Wu HJ (2008) Methylglyoxal and high glucose co-treatment induces apoptosis or necrosis in human umbilical vein endothelial cells. J Cell Biochem 103:1144–1157.PubMedCrossRefGoogle Scholar
  12. 12.
    Oya T, Hattori N, Mizuno Y et al. (1999) Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts. J Biol Chem 274:18492–18502.PubMedCrossRefGoogle Scholar
  13. 13.
    Bucciarelli LG, Kaneko M, Ananthakrishnan R et al. (2006) Receptor for advanced-glycation end products: key modulator of myocardial ischemic injury. Circulation 113:1226–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Thornalley PJ (2003) Glyoxalase I–structure, function and a critical role in the enzymatic defence against glycation. Biochem Soc Trans 31:1343–1348 Review.PubMedCrossRefGoogle Scholar
  15. 15.
    Miyata T, van Ypersele de Strihou C, Imasawa T et al. (2001) Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient. Kidney Int 60:2351–1359.PubMedCrossRefGoogle Scholar
  16. 16.
    Barati MT, Merchant ML, Kain AB et al. (2007) Proteomic analysis defines altered cellular redox pathways and advanced glycation end-product metabolism in glomeruli of db/db diabetic mice. Am J Physiol Renal Physiol 293:F1157–F1165.PubMedCrossRefGoogle Scholar
  17. 17.
    Shinohara M, Thornalley PJ, Giardino I et al. (1998) Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest 101:1142–1147.PubMedCrossRefGoogle Scholar
  18. 18.
    Morcos M, Du X, Pfisterer F et al. (2008) Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans. Aging Cell 7:260–269.PubMedCrossRefGoogle Scholar
  19. 19.
    Creighton DJ, Zheng ZB, Holewinski R et al. (2003) Glyoxalase I inhibitors in cancer chemotherapy. Biochem Soc Trans 31:1378–1382 Review.PubMedCrossRefGoogle Scholar
  20. 20.
    Kumagai T, Nangaku M, Kojima I et al. (2008) Glyoxlase I overexpression ameliorates renal ischemia-reperfusion injury in rats. Am J Physiol Renal Physiol 296(4):F912–F921.CrossRefGoogle Scholar
  21. 21.
    Inagi R, Miyata T, Ueda Y et al. (2002) Efficient in vitro lowering of carbonyl stress by the glyoxalase system in conventional glucose peritoneal dialysis fluid. Kidney Int 62:679–87.PubMedCrossRefGoogle Scholar
  22. 22.
    Ceradini DJ, Yao D, Grogan RH et al. (2008) Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J Biol Chem 283:10930–10938.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Reiko Inagi
    • 1
  • Takanori Kumagai
    • 2
  • Toshiro Fujita
    • 2
  • Masaomi Nangaku
    • 2
  1. 1.Division of Nephrology and EndocrinologyUniversity of Tokyo School of MedicineTokyoJapan
  2. 2.Division of Nephrology and EndocrinologyUniversity of Tokyo School of MedicineTokyoJapan

Personalised recommendations