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Calcium Oxalate Monohydrate is Associated with Endothelial Cell Toxicity But Not with Reactive Oxygen Species Accumulation

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Abstract

One characteristic of ethylene glycol overdose is a cardiopulmonary syndrome including hypertension and pulmonary edema with pathology indicating damage to the endothelium of heart, lung and brain vessels. The mechanism of the cardiopulmonary toxicity is unknown, but has been linked with accumulation of the metabolite calcium oxalate monohydrate (COM) in the endothelium. These studies have evaluated the hypothesis that COM or the oxalate ion produces endothelial damage in vitro and that damage is linked with induction of reactive oxygen species (ROS). In cultured human umbilical vein endothelial cells (HUVEC), COM, but not the oxalate ion, produced cytotoxicity in a dose- and time-dependent manner. Using three ROS-sensitive dyes, HUVEC exposed to COM did not significantly increase ROS production. Additionally, co-treatment with three antioxidants that operate by different mechanisms did not reduce COM cytotoxicity. As such, an increase in ROS production does not explain cell death in endothelial cells. Aluminum citrate, uniquely among citrate compounds, significantly reduced COM cytotoxicity to endothelial cells and thus may act as an adjunct therapy for ethylene glycol poisoning to reduce endothelial damage. These results imply that accumulation of COM in endothelial cells is an important aspect of the cardiopulmonary toxicity from ethylene glycol.

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References

  1. Aruoma, O. I., Halliwell, B., Hoey, B. M., & Butler, J. (1989). The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biology and Medicine, 6, 593–597.

    CAS  PubMed  Google Scholar 

  2. Besenhofer, L. M., Cain, M. C., Dunning, C., & McMartin, K. E. (2012). Aluminum citrate prevents renal injury from calcium oxalate crystal deposition. Journal of the American Society of Nephrology, 23, 2024–2033.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Boogaerts, M. A., Hammerschmidt, D. E., Roelant, C., Verwilghen, R. L., & Jacob, H. S. (1983). Mechanisms of vascular damage in gout and oxalosis: Crystal induced, granulocyte mediated, endothelial injury. Thrombosis and Haemostasis, 50, 576–580.

    CAS  PubMed  Google Scholar 

  4. Colell, A., Garcia-Ruiz, C., Lluis, J. M., Coll, O., Mari, M., & Fernandez-Checa, J. C. (2003). Cholesterol impairs the adenine nucleotide translocator-mediated mitochondrial permeability transition through altered membrane fluidity. Journal of Biological Chemistry, 278, 33928–33935.

    CAS  PubMed  Google Scholar 

  5. Comporti, M. (1989). Three models of free radical-induced cell injury. Chemico-Biological Interactions, 72, 1–56.

    CAS  PubMed  Google Scholar 

  6. Corcoran, G. B., & Wong, B. K. (1986). Role of glutathione in prevention of acetaminophen-induced hepatoxicity by N-acetyl-l-cysteine in vivo. Journal of Pharmacology and Experimental Therapeutics, 238, 54–61.

    CAS  PubMed  Google Scholar 

  7. Corley, R. A., Wilson, D. M., Hard, G. C., Stebbins, K. E., Bartels, M. J., Soelberg, J. J., et al. (2008). Dosimetry considerations in the enhanced sensitivity of male Wistar rats to chronic ethylene glycol-induced nephrotoxicity. Toxicology and Applied Pharmacology, 228, 165–178.

    CAS  PubMed  Google Scholar 

  8. Cotgreave, I., Moldeus, P., & Schuppe, I. (1991). The metabolism of N-acetylcysteine by human endothelial cells. Bioch Pharm., 42, 13–16.

    CAS  Google Scholar 

  9. Cruzan, G., Corley, R. A., Hard, G. C., Mertens, J. J. W. M., McMartin, K. E., Snellings, W. M., et al. (2004). Subchronic toxicity of ethylene glycol in Wistar and F344 rats related to metabolism and clearance of metabolites. Toxicological Sciences, 81, 502–511.

    CAS  PubMed  Google Scholar 

  10. Cuzzocrea, S., Zingarelli, B., Costantino, G., & Caputi, A. (1999). Beneficial effects of Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in carrageenan-induced pleurisy. Free Radical Biology and Medicine, 26, 25–33.

    CAS  PubMed  Google Scholar 

  11. Day, B., Shawen, S., Liochev, S., & Crapo, J. (1995). A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced endothelial cell injury, in vitro. The Journal of Pharmacology and Experimental Therapeutics, 275, 1227–1232.

    CAS  PubMed  Google Scholar 

  12. Diaz, C., Catalinas, F. G., de Alvaro, F., Torre, A., Sanchez, C., & Costero, O. (2004). Long term hemodialysis sessions correct systemic complications of oxalosis prior to combined liver-kidney transplantation: Case report. Therapeutic Apheresis and Dialysis, 8, 52–55.

    PubMed  Google Scholar 

  13. Falasca, G., Ramachandrula, A., Kelley, K., O’Connor, C., & Reginato, A. (1993). Superoxide production and phagocytosis of crystals by cultured endothelial cells. Arthritis and Rheumatism., 36, 105–116.

    CAS  PubMed  Google Scholar 

  14. Friedman, E., Greenberg, J., Merrill, J., & Dammin, G. (1962). Consequences of ethylene glycol poisoning. Report of four cases and review of the literature. The American Journal of Medicine, 32, 891–902.

    CAS  PubMed  Google Scholar 

  15. Froberg, K., Dorion, R. P., & McMartin, K. E. (2006). The role of calcium oxalate crystal deposition in cerebral vessels during ethylene glycol poisoning. Clinical Toxicology, 44, 315–318.

    CAS  PubMed  Google Scholar 

  16. Frommer, J., & Ayus, J. (1982). Acute ethylene glycol intoxication. American Journal of Nephrology, 2, 1–5.

    CAS  PubMed  Google Scholar 

  17. Guo, C., Dugas, T. R., Scates, C., Garcia-Villarreal, M., Ticich, T., & McMartin, K. E. (2013). Aluminum citrate blocks toxicity of calcium oxalate crystals by preventing binding with cell membrane phospholipids. American Journal of Nephrology, 37, 41–49.

    CAS  PubMed  Google Scholar 

  18. Guo, C., & McMartin, K. E. (2005). The cytotoxicity of oxalate, metabolite of ethylene glycol, is due to calcium oxalate monohydrate formation. Toxicology, 208, 347–355.

    CAS  PubMed  Google Scholar 

  19. Guo, C., & McMartin, K. E. (2007). Aluminum citrate inhibits cytotoxicity and aggregation of oxalate crystals. Toxicology, 230, 117–125.

    CAS  PubMed  Google Scholar 

  20. Hantson, P., Vanbist, R., & Mahieu, P. (2002). Determination of ethylene glycol tissue content after fatal oral poisoning and pathologic findings. American Journal of Forensic Medicine and Pathology, 23, 159–161.

    PubMed  Google Scholar 

  21. Hardman, R., Afshari, C., & Barrett, J. (2001). Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress. Cancer Research, 61, 1392–1397.

    CAS  PubMed  Google Scholar 

  22. Hovda, K. E., Guo, C., Austin, R., & McMartin, K. E. (2010). Renal toxicity of ethylene glycol results from internalization of calcium oxalate crystals by proximal tubule cells. Toxicology Letters, 192, 365–372.

    CAS  PubMed  Google Scholar 

  23. Huang, H. S., Ma, M. C., Chen, J., & Chen, C. F. (2002). Changes in the oxidant-antioxidant balance in the kidney of rats with nephrolithiasis induced by ethylene glycol. Journal of Urology, 167, 2584–2593.

    CAS  PubMed  Google Scholar 

  24. Jacobsen, D., & McMartin, K. E. (1986). Methanol and ethylene glycol poisoning. Mechanism of toxicity, clinical course, diagnosis and treatment. Medical Toxicology, 1, 309–334.

    CAS  PubMed  Google Scholar 

  25. Jacobsen, D., Ovrebo, S., Ostborg, J., & Sejersted, O. M. (1984). Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis. Acta Medica Scandinavica, 216, 409–416.

    CAS  PubMed  Google Scholar 

  26. Junod, A., Jornot, L., & Grichting, G. (1987). Comparative study on the selenium- and N-acetyl-cysteine-related effects on the toxic actions of hyperoxia, paraquat and the enzyme reaction hypoxanthine-xanthine oxidase in cultured endothelial cells. Agents and Actions, 22, 177–183.

    Google Scholar 

  27. Khan, S. R. (1995). Calcium oxalate crystal interaction with renal tubular epithelium, mechanism of crystal adhesion and its impact on stone development. Urological Research, 23, 71–79.

    CAS  PubMed  Google Scholar 

  28. Knoll, T., Steidler, A., Trojan, L., Sagi, S., Schaaf, A., Yard, B., et al. (2004). The influence of oxalate on renal epithelial and interstitial cells. Urological Research, 32, 304–309.

    CAS  PubMed  Google Scholar 

  29. Kohjimoto, Y., Kennington, L., Scheid, C. R., & Honeyman, T. W. (1999). Role of phospholipase A2 in the cytotoxic effects of oxalate in cultured renal epithelial cells. Kidney International, 56, 1432–1441.

    CAS  PubMed  Google Scholar 

  30. Laube, N., Jansen, B., & Hesse, A. (2002). Citric acid or citrates in urine: Which should we focus on in the prevention of calcium oxalate crystals and stones? Urological Research, 30, 336.

    CAS  PubMed  Google Scholar 

  31. Levesque, A., Paquet, A., & Page, M. (1995). Improved fluorescent bioassay for the detection of tumor necrosis factor activity. Journal of Immunological Methods, 178, 71–76.

    CAS  PubMed  Google Scholar 

  32. Levin, R., Kantoff, P., & Jaffe, E. (1990). Uremic levels of oxalic acid suppress replication and migration of human endothelial cells. Arteriosclerosis, 10, 198–207.

    CAS  PubMed  Google Scholar 

  33. Loor, G., Kondapalli, J., Schriewer, J. M., Chandel, N. S., Vanden Hoek, T. L., & Schumacker, P. T. (2010). Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radical Biology and Medicine, 15, 1925–1936.

    Google Scholar 

  34. McMartin, K. E. (2009). Are calcium oxalate crystals involved in the mechanism of acute renal failure in ethylene glycol poisoning? Clinical Toxicology, 47, 859–869.

    CAS  PubMed  Google Scholar 

  35. McMartin, K. E., Jacobsen, D., & Hovda, K. E. (2016). Antidotes for poisoning by alcohols that form toxic metabolites. British Journal of Clinical Pharmacology, 81, 505–515.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. McMartin, K. E., & Wallace, K. B. (2005). Calcium oxalate monohydrate, a metabolite of ethylene glycol, is toxic for rat renal mitochondrial function. Toxicological Sciences, 84, 195–200.

    CAS  PubMed  Google Scholar 

  37. Moldeus, P., Cotgreave, I., & Berggren, M. (1986). Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration, 50, 31–42.

    CAS  PubMed  Google Scholar 

  38. Nabeyrat, E., Jones, G., Fenwick, P., Barnes, P., & Donnelly, L. (2003). Mitogen-activated protein kinases mediate peroxynitrite-induced cell death in human bronchial epithelial cells. American Journal of Physiology-Lung Cellular and Molecular Physiology, 284, 1112–1120.

    Google Scholar 

  39. Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., et al. (2005). Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature, 434, 652–658.

    CAS  PubMed  Google Scholar 

  40. Ody, C., & Junod, A. (1985). Direct toxic effects of paraquat and oxygen on cultured endothelial cells. Laboratory Investigation, 52, 77–84.

    CAS  PubMed  Google Scholar 

  41. Pak, C. Y., Sakhaee, K., & Fuller, C. J. (1983). Physiological and physiochemical correction and prevention of calcium stone formation by potassium citrate therapy. Transactions of the Association of American Physicians, 96, 294.

    CAS  PubMed  Google Scholar 

  42. Recht, P., Tepedino, G., Siecke, N., Buckley, M., Mandeville, J., Maxfield, F., et al. (2004). Oxalic acid alters intracellular calcium in endothelial cells. Atherosclerosis, 173, 321–328.

    CAS  PubMed  Google Scholar 

  43. Scheid, C., Koul, H., Hill, W. A., Luber-Narod, J., & Kennington, L. (1996). Oxalate toxicity in LLC-PK1 cells: Role of free radicals. Kidney International, 49, 413–419.

    CAS  PubMed  Google Scholar 

  44. Schepers, M. S. J., Van Ballegooijen, E. S., Bangma, C. H., & Verkoelen, C. F. (2005). Crystals cause acute necrotic death in renal proximal tubule cells, but not in collecting tubule cells. Kidney International, 68, 1543–1553.

    PubMed  Google Scholar 

  45. Schepers, M. S. J., Van Ballegooijen, E. S., Bangma, C. H., & Verkoelen, C. F. (2005). Oxalate is toxic to renal tubule cells only at supraphysiologic concentrations. Kidney International, 68, 1660–1669.

    CAS  PubMed  Google Scholar 

  46. Schnellman, R. G., Yang, X., & Carrick, J. B. (1994). Arachidonic acid release in renal proximal tubule cell injuries and death. Journal of Biochemical Toxicology, 9, 211–217.

    Google Scholar 

  47. Strzelecki, T., McGraw, B. R., Scheid, C. R., & Menon, M. (1989). Effect of oxalate on function of kidney mitochondria. Journal of Urology, 141, 423–427.

    CAS  PubMed  Google Scholar 

  48. Thamilselvan, S., Hackett, R. L., & Khan, S. R. (1997). Lipid peroxidation in ethylene glycol induced hyperoxaluria and calcium oxalate nephrolithiasis. Journal of Urology, 157, 1059–1063.

    CAS  PubMed  Google Scholar 

  49. Thamilselvan, S., Byer, K. J., Hackett, R. L., & Khan, S. R. (2000). Free radical scavengers, catalase and superoxide dismutase provide protection from oxalate-associated injury to LLC-PK1 and MDCK cells. Journal of Urology, 164, 224–229.

    CAS  PubMed  Google Scholar 

  50. Traber, M. G., & Atkinson, J. (2007). Vitamin E, antioxidant and nothing more. Free Radical Biology and Medicine, 43, 4–15.

    CAS  PubMed  Google Scholar 

  51. Tsan, M., Danis, E., del Vecchio, P., & Rosano, C. (1985). Enhancement of intracellular glutathione protects endothelial cells from oxidant damage. Biochemical and Biophysical Research Communications, 127, 270–276.

    CAS  PubMed  Google Scholar 

  52. Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., & Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: A prophylactic approach with fucoidan. European Journal of Pharmacology, 579, 330–336.

    CAS  PubMed  Google Scholar 

  53. Verkoelen, C. F., van der Boom, B. G., Kok, D. J., Houtsmuller, A. B., Visser, P., Schroder, F. H., et al. (1999). Cell type-specific acquired protection from crystal adherence by renal tubule cells in culture. Kidney International, 55, 1426–1433.

    CAS  PubMed  Google Scholar 

  54. Winterbourn, C., & Metodiewa, D. (1999). Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radical Biology and Medicine, 27, 322–328.

    CAS  PubMed  Google Scholar 

  55. Yoshioka, J., Park, Y.-D., Tanaka, Y., Kobayashi, Y., Miyajima, M., Tani, A., et al. (2001). Echocardiographic features in a patient with primary oxalosis. Echocardiography, 18, 599–602.

    CAS  PubMed  Google Scholar 

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Funding

This research was supported by a research agreement with the Ethylene Glycol Panel of the American Chemistry Council and by a Grant from the Louisiana Board of Regents NSF-EPSCoR (NSF(2006)-Pfund-63).

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  1. Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA

    Brian L. Crenshaw & Kenneth E. McMartin

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  1. Brian L. Crenshaw
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  2. Kenneth E. McMartin
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by BC and KM. The first draft of the manuscript was written by Brian Crenshaw and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kenneth E. McMartin.

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These studies were approved by the Institutional Review Board for Human Research at LSU Health Sciences Center-Shreveport and subjects gave informed consent for the use of their discarded tissue (umbilical veins).

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Crenshaw, B.L., McMartin, K.E. Calcium Oxalate Monohydrate is Associated with Endothelial Cell Toxicity But Not with Reactive Oxygen Species Accumulation. Cardiovasc Toxicol 20, 593–603 (2020). https://doi.org/10.1007/s12012-020-09584-4

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