Ukr.Biochem.J. 2022; Volume 94, Issue 1, Jan-Feb, pp. 23-32


Rhabdomyolysis attenuates activity of semicarbazide sensitive amine oxidase as the marker of nephropathy in diabetic rats

O. Hudkova*, I. Krysiuk, L. Drobot, N. Latyshko

Department of Cell Signaling, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;

Received: 22 December 2021; Accepted: 21 January 2022

Amine oxidases are involved in the progression of many diseases and their complications, including renal failure, due to the generation of the three toxic metabolites (H2O2, aldehydes, and ammonia) in the course of biogenic amines oxidative deamination. The participation of the first two products in kidney pathogenesis was confirmed, whereas the role of ammonia as a potential inducer of the nitrozative stress is not yet understood. The aim of the present study was to test how further intensification of oxidative stress would affect diabetes-mediated metabolic changes. For this purpose, a rat model of glycerol-induced rhabdomyolysis, as a source of powerful oxidative stress due to the release of labile Fe3+ from ruptured myocytes, on the background of streptozotocin-induced diabetes was used. The experimental animal groups were as follows: group 1 – ‘Control’, group 2 – ‘Diabetes’, group 3 – ‘Diabetes + rhabdomyolysis’. A multifold increase in semicarbazide sensitive amine oxidase (SSAO) activity in the kidney and blood, free radicals (FR), MetHb and 3-nitrotyrosine (3-NT) levels in the blood, as well as the emergence of HbNO in plasma and dinitrosyl iron complexes (DNICs) in the liver of animals in group 2 as compared to control were revealed. An additional increase in FR, HbNO levels in the blood, and DNICs in the liver of animals in the diabetes + rhabdomyolysis group as compared to the diabetes group, which correlated with the appearance of a large amount of Fe3+ in the blood of group 3 animals, was detected. Unexpectedly, we observed the positive regulatory effects in animals of the diabetes + rhabdomyolysis group, in particular, a decreased SSAO activity in the kidney and 3-NT level in plasma, as well as the normalization of activity of pro- and antioxidant enzymes in the blood and liver compared to animals of diabetes group. These consequences mediated by rhabdomyolysis may be the result of NO exclusion from the circulation due to the excessive formation of NO stable complexes in the blood and liver. The data obtained allow us to consider SSAO activity as a marker of renal failure in diabetes mellitus. In addition, we suggest a significant role of nitrosative stress in the development of pathology, and, therefore, recommend NO-traps in the complex treatment of diabetic complications.

Keywords: , , , , ,


  1. Sánchez-Jiménez F, Ruiz-Pérez MV, Urdiales JL, Medina MA. Pharmacological potential of biogenic amine-polyamine interactions beyond neurotransmission. Br J Pharmacol. 2013;170(1):4-16. PubMed, PubMedCentral, CrossRef
  2. Boomsma F, Bhaggoe UM, van der Houwen AM, van den Meiracker AH. Plasma semicarbazide-sensitive amine oxidase in human (patho)physiology. Biochim Biophys Acta. 2003;1647(1-2):48-54. PubMed, CrossRef
  3. Obata T. Semicarbazide-sensitive amine oxidase (SSAO) in the brain. Neurochem Res. 2002;27(4):263-268. PubMed, CrossRef
  4. Cooper amine oxidases. Structure, catalytic mechanisms and role in pathophisiology. Ed. by G. Floris, B. Mondovi. CRC Press, 2009. 374 p.
  5. Hernandez-Guillamon M, Solé M, Delgado P, García-Bonilla L, Giralt D, Boada C, Penalba A, García S, Flores A, Ribó M, Alvarez-Sabin J, Ortega-Aznar A, Unzeta M, Montaner J. VAP-1/SSAO plasma activity and brain expression in human hemorrhagic stroke. Cerebrovasc Dis. 2012;33(1):55-63.
    PubMed, CrossRef
  6. Wu G,Bazer FW, Davis TA, Kim SW, Li P, Rhoads JM, Satterfield MC, Smith SB, Spencer TE, Yin Y. Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 2009;37(1):153-168. PubMed, PubMedCentral, CrossRef
  7. Levillain O, Hus-Citharel A, Morel F, Bankir L. Localization of arginine synthesis along rat nephron. Am J Physiol. 1990;259(6 Pt 2):F916-F923. PubMed, CrossRef
  8. Morris SM Jr. Arginine metabolism: boundaries of our knowledge. J Nutr. 2007;137(6 Suppl 2):1602S-1609S. PubMed, CrossRef
  9. Brosnan ME, Brosnan JT. Renal arginine metabolism. J Nutr. 2004;134(10 Suppl):2791S-2795S. PubMed, CrossRef
  10. Wang JY and Casero RA. Polyamine cell signaling: Physiology, Pharmacology, and Cancer Research. 2006; Humana Press. 490 p. CrossRef
  11. Han KH, Jung JY, Chung KY, Kim H, Kim J. Nitric oxide synthesis in the adult and developing kidney. Electrolyte Blood Press. 2006;4(1):1-7. PubMed, PubMedCentral, CrossRef
  12. Baylis C. Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol. 2008;294(1):F1-F9. PubMed, CrossRef
  13. Pacher P, Obrosova IG, Mabley JG, Szabó C. Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem. 2005;12(3):267-275. PubMed, PubMedCentral, CrossRef
  14. Weiner ID, Mitch WE, Sands JM. Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion. Clin J Am Soc Nephrol. 2015;10(8):1444-1458. PubMed, PubMedCentral, CrossRef
  15. Gudkova OO, Latyshko NV, Shandrenko SG. Amine oxidases as important agents of pathological processes of rhabdomyolysis in rats. Ukr Biochem J. 2016;88(1):79-87. PubMed, CrossRef
  16. Kitada M, Ogura Y, Koya D. Rodent models of diabetic nephropathy: their utility and limitations. Int J Nephrol Renovasc Dis. 2016;9:279-290. PubMed, PubMedCentral, CrossRef
  17. Latyshko N, Gudkova O, Dmytrenko M. Semicarbazide as potential source of formaldehyde and nitric oxide formation. Drugs Therapy Studies. 2012;2(e9):43-47. CrossRef
  18. Anderson RF, Patel KB, Reghebi K, Hill SA. Conversion of xanthine dehydrogenase to xanthine oxidase as a possible marker for hypoxia in tumours and normal tissues. Br J Cancer. 1989 Aug;60(2):193-197. PubMed, PubMedCentral, CrossRef
  19. Gudkova OO, Latyshko NV, Gudkova LV, Mikhailovsky VO. Rat liver catalase under artificial hypobiosis conditions. Biopolym Cell. 2005;21(1):28-34. CrossRef
  20. Eriksson UJ, Borg LA. Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro. Diabetologia. 1991;34(5):325-331. PubMed, CrossRef
  21. Beers RF Jr, Sizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 1952;195(1):133-140. PubMed
  22. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179(4073):588-590.
    PubMed, CrossRef
  23. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254. PubMed, CrossRef
  24. Slack AJ, Wendon J. The liver and kidney in critically ill patients. Blood Purif. 2009;28(2):124-134. PubMed, CrossRef
  25. Slack A,Yeoman A, Wendon J. Renal dysfunction in chronic liver disease. Crit Care. 2010;14(2):214. PubMed, PubMedCentral, CrossRef
  26. Lambert MP. Platelets in liver and renal disease. Hematology Am Soc Hematol Educ Program. 2016;2016(1):251-255. PubMed, PubMedCentral, CrossRef
  27. Tokarchuk K, Krysyuk I, Shandrenko S. Changes of Carbonyl Stress Parameters in Rats with Diabetes and Rhabdomyolysis. Int J Biochem Res Rev. 2015;6(4):151-159.
  28. Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene. 2003;22(37):5734-5754. PubMed, CrossRef
  29. Tian S, Liu J, Cowley RE, Hosseinzadeh P, Marshall NM, Yu Y, Robinson H, Nilges MJ, Blackburn NJ, Solomon EI, Lu Y. Reversible S-nitrosylation in an engineered azurin. Nat Chem. 2016;8(7):670-677. PubMed, PubMedCentral, CrossRef
  30. Radicals for Life: the Various Forms of Nitric Oxide. Eds. van Faassen E, Vanin AF. Elsevier Science, 2007. 442 p. CrossRef
  31. Habib S, Ali A. Biochemistry of nitric oxide. Indian J Clin Biochem. 2011;26(1):3-17. PubMed, PubMedCentral, CrossRef
  32. Bleier L, Dröse S. Superoxide generation by complex III: from mechanistic rationales to functional consequences. Biochim Biophys Acta. 2013;1827(11-12):1320-1331. PubMed, CrossRef
  33. Gödecke A. On the impact of NO-globin interactions in the cardiovascular system. Cardiovasc Res. 2006;69(2):309-317. PubMed, CrossRef
  34. Buenger JW, Mauro VF. Organic nitrate-induced methemoglobinemia. DICP. 1989;23(4):283-288. PubMed, CrossRef
  35. Zotti FD, Lobysheva II, Balligand JL. Nitrosyl-hemoglobin formation in rodent and human venous erythrocytes reflects NO formation from the vasculature in vivo. PLoS One. 2018;13(7):e0200352. PubMed, PubMedCentral, CrossRef

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