Mechanism of hepatorenal syndrome in rats of Long-Evans Cinnamon strain, an animal model of fulminant Wilson's disease.
Rats of Long-Evans Cinnamon (LEC) strain were used as a hepatorenal syndrome model of fulminant Wilson's disease. Copper levels in the kidneys increased markedly from 16 to 126 microg Cu/g from 12 to 16 weeks, and remained at the same level at 16 and 19 weeks when the rats suffered from severe renal dysfunction and also at 20 weeks in some other normal rats. The above findings imply that the renal dysfunction may have been induced independently of the copper level in the kidneys. The present study suggested the following mechanism: immediately after copper-induced hepatic dysfunction, plasma copper-metallothionein (CuMT), which was released from the liver, became elevated. The elevation was closely related to the increases in alkaline phosphatase, glucose and amino acids, all in the urine. The above findings suggest that plasma CuMT, which was released from the liver into the blood upon copper-induced hepatic dysfunction, was subsequently filtered at the glomeruli due to its smaller molecular weight, and then caused dysfunction of the brush border membrane of the renal proximal tubules probably after splitting into radical copper and amino acids in acidic vesicles close to the membrane. The critical concentration of plasma CuMT required to induce renal dysfunction was estimated as 1 microg Cu/l.
Nomiyama
K
K
Department of Environmental Health, Jichi Medical School, Japan. nomiyama@jichi.ac.jp
Nomiyama
H
H
Kameda
N
N
Tsuji
A
A
Sakurai
H
H
D000818:Animals; D003300:Copper / Q000378:metabolism / Q000633:toxicity*; D004195:Disease Models, Animal; D006527:Hepatolenticular Degeneration / Q000209:etiology* / Q000378:metabolism; D006530:Hepatorenal Syndrome / Q000209:etiology*; D007565:Jaundice / Q000139:chemically induced; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans
D003300:Copper; D008668:Metallothionein