Protective effect of L-propionylcarnitine on cyclosporine-induced nephrotoxicity.
Nephrotoxicity has represented the major limitation in the use of cyclosporine A (CyA). The structural abnormalities at the level of the proximal tubular cells are necrosis, vacuolisation and lipid droplets, as well as CyA-induced glomerular afferent arteriole constriction and granular juxtaglomerular cell hyperplasia. The mode of action of vasoconstriction is not well known, but there appears to be substantial impairment of endothelial cell function leading to enhanced release of vasoconstrictors such as endothelin and thromboxane. L-propionylcarnitine (PC), one of the most potent analogues of carnitine, is able to correct and to prevent alterations in endothelial membrane permeability and it has been identified in the kidney of various animal species. To investigate a possible reduction of CyA-induced nephrotoxocity, we examined the effects of a pretreatment with PC before administering several doses of CyA in an isolated and perfused rat kidney. The histological findings showed that the perfusion with PC reduces the vasoconstrictive effect of CyA on the glomerular capillaries and preserves the tubular epithelium. The ratio of the diameter between the glomerular capillary tuft and Bowman's capsule was higher, while at the tubular level the ratio internal-diameter/diameter evaluated at the level of the basal membrane was lower in PC + CyA perfused kidneys than in only CyA perfused ones. The final value of perfusion pressure was lower in PC + CyA perfused kidneys than in only CyA perfused ones, confirming the histological findings. The release induced by CyA of alanine aminopeptidase (AAP) and N-acetyl-glucosaminidase (NAG), markers of tubular damage, was significantly reduced by pretreatment with PC. These data suggest that the pretreatment with PC reduces the CyA-induced nephrotoxicity in an isolated and perfused rat kidney.
Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Italy.
A
A
Bertelli
L
L
Giovannini
R
R
Palla
M
M
Migliori
V
V
Panichi
B
B
Andreini
D000704:Analysis of Variance; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016572:Cyclosporine / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
C003223:propionylcarnitine; D016572:Cyclosporine; D002331:Carnitine