Different effect of cyclosporine A and mycophenolate mofetil on passive Heymann nephritis in the rat

While cyclosporine A (CsA) is an effective therapy for nephrotic syndrome, it has nephrotoxic side effects. We compared the anti-proteinuric effects and nephrotoxicity in rats with passive Heymann nephritis (PHN) of CsA and mycophenolate mofetil (MMF).

PHN was induced in female Wistar rats. Two treatment groups consisting of 8 rats each received either 25 mg of CsA or 25 mg of MMF/kg body weight/day and were compared with untreated controls. Kidney function and proteinuria were monitored over 4 weeks. Western blots were used for densitometric analysis of renal cyclooxygenase-2 (COX-2) protein expression. Thromboxane B2 (TxB2) and 6-keto-PGF(1alpha) were determined by radioimmunoassays (RIAs) in renal tissue and urine.

Rats with PHN exhibited a marked proteinuria of 12.76 +/- 4.42 vs. 0.73 +/- 0.28 mg/24 h (p < 0.01) and showed increased glomerular concentrations of TxB2 and 6-keto-PGF(1alpha) (992.6 +/- 216.9 and 1,187.0 +/- 54.2 pg/mg protein, respectively) compared with healthy controls (595 +/- 196.17 and 729 +/- 297.84, respectively) and a strongly induced COX-2 protein expression. CsA and MMF treatment reduced PHN-related proteinuria to 2.10 +/- 1.47 and 1.47 +/- 7.2 mg/24 h, respectively. In rats with PHN, CsA induced a significant deterioration of renal function and enhanced urine excretion of thromboxane A2, paralleled by a significant, twofold increase in COX-2 protein expression and renal prostaglandins. By contrast, MMF treatment in rats with PHN was not nephrotoxic and had no effect on prostaglandin production. COX-2 protein expression under MMF was suppressed.

While the antiproteinuric efficacy of MMF and CsA in PHN was comparable, the absence of nephrotoxicity might favor MMF in the treatment of nephrotic syndrome. The CsA-induced increase in COX-2 expression and COX-2-dependent prostacyclin may indicate a mechanism that compensates nephrotoxicity in the diseased and CsA-exposed kidney.