Site of methylguanidine production and factors that influence production levels.
The site of methylguanidine (MG) production in the kidney was investigated using animal models of renal disease and cultured renal epithelial cells. In rats with proximal tubular injury induced by adenine, the blood and urinary levels of MG increased as the severity of injury increased. In contrast, in cases of glomerular injury, there were no such changes in MG levels. Thus, it was apparent that proximal tubular injury served to promote MG production. In addition, a marked increase was observed in the intensities of bands attributable to 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-OH in the electron spin resonance spectrum of the kidney in the rats given adenine. In these rats, the activity of the radical-scavenging enzymes superoxide dismutase, catalase, and glutathione peroxidase was decreased. This suggests that the formation of excessive radicals and deterioration of defense mechanisms that contribute to the development of oxidative stress underlie the enhanced MG production. The experiments using cultured cells revealed that an oxide of adenine, 2,8-dihydroxyadenine (DHOA), directly induced renal tubular injury. These findings indicate that the accumulation of creatinine due to DHOA, combined with oxidative stress, resulted in increased MG production.
Yokozawa
Takako
T
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitami, Toyama 930-0194, Japan. yokozawa@ms.toyama-mpu.ac.jp
Muto
Yasuko
Y
Wakaki
Kunihiko
K
Kashiwagi
Hiroshi
H
D000225:Adenine / Q000633:toxicity; D000818:Animals; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000293:injuries / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000293:injuries / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D008760:Methylguanidine / Q000378:metabolism*; D009392:Nephrectomy; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism; D013113:Spin Labels; D014018:Tissue Distribution; D014511:Uremia / Q000209:etiology / Q000378:metabolism
D003497:Cyclic N-Oxides; D005609:Free Radicals; D013113:Spin Labels; D008760:Methylguanidine; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D000225:Adenine