Abstract
Synthesis of guanidinosuccinic acid (GSA) and methylguanidine (MG) is markedly increased in end-stage renal disease (ESRD), and these substances have been known as uremic toxins.
GSA has been identified as one of the major causes of bleeding tendency, a Na-K ATPase inhibitor, and the cause of convulsions in ESRD. Recently, GSA (N-amidino-l-aspartate) was found to be an activator of theN-methyl-d-aspartate (NMDA) receptor that generates NO and plays an important role in nerve development and the death of neurons. In peripheral nerves, it functions in pain and itching sensations. I have shown that GSA is formed from ASA and the hydroxyl radical. The combination of NO and superoxide anion also generates GSA. Thus, in the system involving the GSA-NMDA receptor-NO+O2 −, GSA may act as an amplifier of reactive oxygen generation. MG, another major uremic toxin, causes hypertension and a shortening of the life span. We have also shown that MG is formed through the hydroxyl adduct of creatinine (creatol). Therefore, MG and/or creatol can be used to estimate hydroxyl radical generation. We reported a marked increase of creatol synthesis in severely hyperparathyroid patients. Additionally, using this method we demonstrated an increase in hydroxyl radical generation by puromycin aminonucleoside (PAN), which induces heavy proteinuria. We further showed that the increased hydroxyl radical generation induced by PAN was caused by the activation of calcium-dependent protein kinase C (PKC) and was prevented by the inhibitors of PKC. We also showed increased hydroperoxides in PAN-treated glomeruli. Thus, increased MG and GSA may indicate hydroxyl radical generation in renal failure.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Cohen B, Stein I, Bonas J. Guanidinosuccinic aciduria in uremia. A possible alternate pathway for urea synthesis. Am J Med 1968;45:63–68
Horowitz HI, Stein IM, Cohen BD, White JG. Further studies on the platelet-inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding. Am J Med 1970;49:336–345
D'Hoogg R, Raes A, Lebrun P, Diltoer M, Van Bogaert PP, Manil J, Colin F, DeDeyn PP.N-Methyl-D-aspartate receptor activation by guanidinosuccinate but not by methylguanidine: behavioural and electrophysiological evidence. Neuropharmacology 1996;35: 433–440
Pan JC, Pei YQ, An L, Lai L, D'Hooge R, De Deyn PP. Epileptiform activity and hippocampal damage produced by intrahippocampal injection of guanidinosuccinic acid in rat. Neurosci Lett 1996;209:121–124
Kopple JD, Gordon SI, Wang M, Swendseid ME. Factors affecting serum and urinary guanidinosuccinic acid level in normal and uremic subjects. J Lab Clin Med 1968;90:303–311
Aoyagi K, Ohba S, Narita M, Tojo S. Regulation of biosynthesis of guanidinosuccinic acid in isolated rat hepatocytes and in vivo. Kidney Int 1983;24(suppl 16):S224-S228
Menyhart J, Grof J. Urea as a selective inhibitor of argininosuccininate lyase. Eur J Biochem 1977;75:405–409
Aoyagi K, Nagase S, Tomida C, Takemura K, Akiyama K, Koyama A. Synthesis of guanidinosuccinate from argininosuccinate and reactive oxygen in vitro. Enzyme Pro 1996;149:199–204
Aoyagi K, Nagase S, Gotoh M, Akiyama K, Satoh M, Hirayama A, Koyama A. Role of reactive oxygen and argininosuccinate in guanidinosuccinate synthesis in isolated rat hepatocytes. Enzyme Pro 1996;49:205–211
Aoyagi K, Akiyama K, Shahrzad S, Tomida C, Hirayama A, Nagase S, Takemura K, Koyama A, Ohba S, Narita M. Formation of guanidinosuccinic acid, a stable nitric oxide mimic, from argininosuccinic acid and nitric oxide derived free radicals. Free Rad Res 1999;31:59–65
Aoyagi K, Shahrzad S, Iida S, Tomida C, Hirayama A, Nagase S, Takemura K, Koyama A, Ohba S, Narita M, Cohen BD. Role of nitric oxide in the synthesis of guanidinosuccinic acid, an activator of theN-methyl-d-aspartate receptor. Kidney Int 2001;59(suppl 78):93–96
Giovannetti S, Biagini M, Balestri PL, Navalesi R, Giagnoni P, de Matleis A, Ferro-Milone P, Perffetti C. Uremia-like syndrome in dogs chronically intoxicated with methylguanidine and creatinine. Clin Sci 1969;36:445–445
Aoyagi K, Nagase S, Narita M, Tojo S. Role of active oxygen on methylguanidine synthesis in isolated rat hepatocytes. Kidney Int 1987;22:S229-S233
Nakamura K, Lenaga K. Creatol (5-hydroxycreatinine), a new toxin candidate in uremic patients. Experientia 1990;46:470–472
Aoyagi K, Nagase S, Koyama A, Narita M, Tojo S. Products of creatinine with hydroxyl radical as a useful marker of oxidative stress in vivo. In: Armstrong D (ed) Methods in molecular biology. vol. 108: Protocols free radical and antioxidant NJ, USA: Humana Press, 1998;157–164
Aoyagi K, Akiyama K, Kuzure Y, Takemura K, Nagase S, Ienaga K, Nakamura K, Koyam A, Narita M. Synthesis of creatol, a hydroxyl radical adduct of creatinine and its increase by puromycin aminonucleoside in isolated rat hepatocytes. Free Rad Res 1998;29:221–226
Aoyagi K, Nagase S, Takemura K, Ohba S, Narita M. Dipyridamole decreased urinary excretion of methylguanidine increased by puromycin aminonucleoside in vivo. In: DeDeyn PP, Marescau B, Stalon V, Qureshi IA (eds) Guanidino compounds in biology and medicine. London: John Libbey & Company, 1992; 309–313
Aoyagi K, Akiyama K, Tomida C, Gotoh M, Hirayama A, Takemura K, Ueda A, Nagase S, Koyama A, Narita M. Imaging of hydroperoxides in a rat glomerulus stimulated by puromycin aminonucleoside. Kidney Int 1999(suppl 71):S153-S155
Aoyagi K, Kuzure Y, Nagase S, Akiyama K, Koyama A. Rapid activation of protein kinase C of kidney and abnormal reactive oxygen generation by puromycin aminonucleoside in rats (abstract). Nephrology 1997;1:S387
Aoyagi K, Takemura K, Tomida C, Goto M, Koyama A, Narita M. Inhibition of methylguanidine synthesis in isolated rat hepatocytes by protein kinase C inhibitor and calmodulin antagonist. In: DeDeyn PP, Marescau B, Qureshi IA, Mori A (eds) Guanidino compounds in biology and medicine 2. London: John Libbey & Company, 1997;311–316
Aoyagi K, Shahrzad S, Kuzure Y, Koyama A, Nakamura K, Ienaga K. The role of protein kinase C in the increased generation in isolated rat hepatocytes of the hydroxyl radical by puromycin aminonucleoside. Free Rad Res 2000;32:487–496
Aoyagi K, Nagase S, Sakamoto M, Tojo S. Adenosine, adenosine analogues and their potentiators inhibit methylguanidine synthesis, a possible marker of active oxygen in isolated rat hepatocytes. In: Mori A, Cohen BD, Koide H (eds) Guanidines 2. New York: Plenum, 1989;123–128
Aoyagi K, Akiyama K, Yamaguti N, Tomida C, Shahrdad S, Hirayama A, Takemura K, Nagase S, Koyama A, Ohba S, Narita M. Increase of hydroxyradical generation and its time course in streptozotocin-treated rats: estimation by urinary creatol and methylguanidine amount. In: Itoh K, Genba M, Aoyagi K (eds) Kidney and free radical vol 5. Tokyo: Tokyo Igakusya, 2000;92–93 (in Japanese)
Tomida C, Aoyagi K, Nagase S, Gotoh M, Yamagata K, Takemura K, Koyama A. Creatol, an oxidative product of creatinine in hemodialysis patients. Free Rad Res 2000;32:85–92
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Aoyagi, K. Significance of reactive oxygen in kidney disease elucidated by uremic toxins. J Artif Organs 4, 3–7 (2001). https://doi.org/10.1007/BF01235827
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01235827