PROTECTIVE EFFECT OF L-PROPIONYLCARNITINE ON CYCLOSPORINE-INDUCED NEPHROTOXICITY

Nephrotoxicity has represented the major limitation in the use of cycl osporine A (CyA). The structural abnormalities at the level of the pro ximal tubular cells are necrosis, vacuolisation and lipid droplets, as well as CyA-induced glomerular afferent arteriole constriction and gr anular juxtaglomerular cell hyperplasia. The mode of action of vasocon striction is not well known, but there appears to be substantial impai rment of endothelial cell function leading to enhanced release of vaso constrictors such as endothelin and thromboxane. L-propionylcarnitine (PC), one of the most potent analogues of carnitine, is able to correc t and to prevent alterations in endothelial membrane permeability and it has been identified in the kidney of various animal species. To inv estigate a possible reduction of CyA-induced nephrotoxocity, we examin ed 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 vasoconstrictiv e effect of CyA on the glomerular capillaries and preserves the tubula r epithelium. The ratio of the diameter between the glomerular capilla ry tuft and Bowman's capsule was higher, while at the tubular level th e ratio internal-diameter/diameter evaluated at the level of the basal membrane was lower in PC + CyA perfused kidneys than in only CyA perf used ones. The final Value of perfusion pressure was lower in PC + CyA perfused kidneys than in only CyA perfused ones, confirming the histo logical 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 i n an isolated and perfused rat kidney.