Different Effect of Cyclosporine A and Mycophenolate Mofetil on Passive Heymann Nephritis in the Rat

Abstract

Background: 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). Methods: 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_1α were determined by radioimmunoassays (RIAs) in renal tissue and urine. Results: 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_1α (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. Conclusion: 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.

Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy

“…26 Antiproteinuric properties of CsA have been demonstrated both in patients with MN and in Heymann nephritis. 36,37 Accordingly, we show that CsA reduces proteinuria in PHN, in parallel with the downregulation of c-mip and ILK. Although we cannot exclude that an antiproteinuric effect could be due to its immunosuppressive action, we found that CsA restores nephrin and synaptopodin abundances in the podocytes.…”

Replacement of Calcineurin-Inhibitors With Sirolimus as Primary Immunosuppression in Stable Cardiac Transplant Recipients

“…The majority of the literature regarding this concern is derived from patients with chronic kidney allograft dysfunction and were either case series or case reports, measuring proteinuria pre-and postconversion to SRL after withdrawal of CNI without controls (34,35), (36). The mechanism of SRL-associated proteinuria is multifactorial and may be due to an increase in glomerular capillary pressure after CNI withdrawal (37,38). There is also significant correlation between the degree of proteinuria and the concentration of CNI (39).…”

Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro

“…Approximately one-third of patients may develop progressive renal disease. 6 Triptolide, an active component of the medicinal plant Tripterygium wilfordii Hook F (TWHF), 7 has potent immunosuppressive and anti-inflammatory therapeutic effects. Triptolide has been shown to inhibit the proliferation of lymphocytes and induces apoptosis of lymphocytes and dendritic cells.…”