Effects of immunosuppresants on the activated-T cell infiltration mediating progression of glomerular lesions

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We investigated the effect of Tacrolimus (FK506) and Cyclosporin A (CyA) on experimental focal glomerulosclerosis (FGS) in rats. FGS developed in heminephrectomized 10 to 12 week-old male Sprague-Dawley rats by eight repeated injection of puromycin aminonucleosid (PAN) and protamine sulfate (PS). Ten days after the last injection, FK506 (1.0mg/kg/day, 0.3mg/kg/day, 0.1mg/kg/day), CyA (10mg/kg/day, 3mg/kg/day) or vehicle was administered intramuscularly (i.m.) in each group for 56 days. Urinary protein excretion and renal function were examined every two weeks. Rats were sacrificed at day 80. We evaluated interstitial infiltration of leucocytes by an immunoperoxidase staining. Both FK506 and CyA reduced urinary protein excretion dependent to their doses. On the other hand, blood urea nitrogen (BUN) level elevated in all administered groups. At a dose of FK506 1.0mg/kg/day or CyA 10mg/kg/day, serum creatinine (sCr) levels elevated and creatinine clearance (CCr) decreased significantly. In these two groups, tubular injuries and interstitial fibrosis were obviously founded. Meanwhile CyA 3mg/kg/day, FK506 0.3mg/kg/day or 0.1mg/kg/day administered groups showed the decrease of urinary protein. Number of common leucocyte antigen positive cells were not inhibited in any groups. Interleukin-2 receptor (IL-2r) positive cells were decreased significantly in FK506 0.3 or 0.1 mg/kg/day groups. We conclud that optimal dose of both drugs are available for renal disease and avoid serious nephrotoxicity.