Morphological and biochemical observations in rat nephron epithelia following cyclosporine A (CsA) treatment.

Morphology, urinary enzyme excretion and mitochondrial function was studied in rats fed over a period of 30 days with 20 and 40 mg CsA/kg body weight. Already on day 8 vacuolisation and augmentation of autophagic vacuoles, lipid droplets and a loss in microvilli can be observed in the S-3 segment of the proximal nephron using the lower CsA dose. These effects are enhanced during the treatment period. The overall effect, however, is a subtle one. The dose of 40 mg/kg produces more pronounced cellular alterations, a more severe vacuolisation, but also focal prenecrotic damage of proximal tubular S-2 and S-3 cells. The cells altered in that manner amount to roughly 5% of the total proximal tubular epithelium. Enhanced urinary excretion of the proximal cytosolic enzymes, fructose-1,6-bisphosphatase, glutathione S-transferase, pyruvate kinase and the lysosomal N-acetyl-beta-D-glucosaminidase appear to parallel the morphologic changes, whereby only the excretion of pyruvate kinase is significantly elevated on day 30 using 40 mg/kg. Decrease in oxidative phosphorilation capacity (ADP:O ratio) was found with both CsA doses, however, this result seems to be dissociated from changes in morphology and enzyme excretion. Studies on isolated tubular fragments in vitro, exposed to CsA exhibited an inhibition of the cytosolic malate dehydrogenase isoenzyme, which could be interpreted as a possible source of the CsA induced tubular alteration.