Effect of cyclosporin on kidney proteolytic enzymes in men and rats

Cyclosporin (CsA) induces autophagolysosomes in proximal tubules. A major lysosomal function is degradation of cell proteins. Cathepsin B and L are marker enzymes for the activity of lysosomal protein degradation. Therefore we measured cathepsin activities in microdissected proximal tubule segments and urine from rats treated with CsA, 30 mg/24 h by gavage for 42 days. Cathepsin activity was increased in proximal tubule by 117% and in 24-h urine by 37% compared to controls. Unchanged values of serum cathepsin activity and of proteinuria excluded increased glomerular filtration or decreased tubular absorption as major source of urine cathepsins. Therefore urine cathepsin excretion reflected tubular cathepsin activity. Urine cathepsin excretion was also measured in patients without renal disease treated with CsA for multiple sclerosis (MS). It was increased by 59% in patients with CsA serum values > 120 ng/ml compared to MS patients without CsA or with serum CsA < 120 ng/ml. Urine cathepsin excretion increased linearly with serum CsA (P < 0.001). The data suggest that cathepsin activity is increased in proximal tubules of CsA-treated patients. Hence CsA may stimulate protein degradation in proximal tubules of men and rats.