Dissociation of decreases in renal cellular energetics and recovery of renal microsomal translation during chronic cyclosporine a administration

Abstract

Male Sprague-Dawley rats were given oral cyclosporine A or control vehicle, and renal protein synthesis and renal ATP levels were examined. Acute oral cyclosporine A at 5, 10, 25 and 50 mg/kg/day for 6 days reduced [ 3H] L-leucine incorporation by isolated renal microsomes to 76.2, 56.8, 44.3 and 29.5% of control incorporations, respectively. No significant changes in renal ATP levels were detected by NMR spectroscopy after acute oral cyclosporine A administration at the doses indicated. However, during chronic exposure to cyclosporine A at doses of 5 and 25 mg/kg day for 30, 60 and 90 days, there was a recovery of renal microsomal protein synthesis by day 30 at 5 mg/kg/day, and by day 45 at 25 mg/kg/day. NMR spectroscopy of the kidneys of these rats demonstrated decreases in renal ATP level by day 60 in animals given cyclosporine A at 25 mg/kg/day. Cyclosporine A administration produced a renal acidosis and up to a 40% decrease in renal ATP level by day 90 in rats fed cyclosporine A at 25 mg/kg. No apparent histologic abnormalities were observed in the ATP deficient renal tissue by NMR imaging. Reductions in renal ATP level suggest that the recovery of renal microsomal protein synthesis is aberrant in the continued presence of cyclosporine A, or that mitochondria are direct sites of cyclosporine A toxicity.