In vivo and in vitro rat model for cyclosporine-induced proximal tubular toxicity.
Cyclosporine is used widely to prevent transplant rejection. Unfortunately, this drug causes both renal glomerular and tubular damage. To develop a stable reproducible noncatabolic animal model of cyclosporine nephrotoxicity, rats were fed a special liquid diet and daily administered 7.5 mg/kg of cyclosporine intramuscularly. Twenty-one days after this regimen was started, the body weight of cyclosporine-treated rats had increased 15%, a value only 38% less than the increase in pair-fed controls. After 21 days, glomerular filtration rate fell 34% in cyclosporine-treated rats (p less than 0.001) compared with the pair-fed controls. Simultaneously, citrate and N-acetylglucosaminidase excretion increased significantly. When isolated proximal tubules obtained after 21 days from the cyclosporine and pair-fed rats were incubated by using 1.0 mmol/L glutamine and 1.0 mmol/L citrate substrates, ammonia production was reduced 40% and glucose production reduced 20% (p less than 0.001) in the cyclosporine-treated rats. Discontinuing cyclosporine for 7 days partially reversed all these changes. The glomerular filtration rate in cyclosporine-treated rats now was only 15% below that in controls (p less than 0.05), N-acetylglucosaminidase excretion was the same in both groups, and urinary citrate excretion in the cyclosporine-treated rats fell from 122% to 62% above that in controls. In vitro differences in tubular ammonia and glucose production also narrowed. In summary, these experiments describe a stable reproducible noncatabolic and at least partially reversible rat model for studying cyclosporine nephrotoxicity.
Berty
R M
RM
Montefiore Hospital, Pittsburgh, PA 15213.
Adler
S
S
D000118:Acetylglucosaminidase / Q000652:urine; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D002951:Citrates / Q000652:urine; D019343:Citric Acid; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D005943:Gluconeogenesis; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains
D002951:Citrates; D003524:Cyclosporins; D019343:Citric Acid; D000641:Ammonia; D000118:Acetylglucosaminidase