Proinflammatory effects in experimental mesangial proliferative glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin derivative

Background/Aim: The new immunosuppressant SDZ RAD, a rapamycin derivative, inhibits growth factor driven cell proliferation. SDZ RAD designed for tran splantation may also be a candidate agent to treat inflammatory kidney dise ases. Therefore, we investigated the effects of SDZ RAD in two different an imal models of glomerulonephritis, in anti-Thy1.1 nephritis and in acute pu romycin aminonucleoside (PAN) nephrosis. Methods: Eighty-seven male Wistar rats were investigated. Anti-Thy1.1 nephritis: healthy rats (n = 9), SDZ RA D-treated healthy rats (n = 6), nephritic rats (n = 9), SDZ RAD placebo tre ated nephritic rats (n = 6), SDZ RAD-pretreated nephritic rats (n = 9), and early (n = 6) as well as delayed (n = 6) SDZ RAD-posttreated nephritic rat s. PAN nephrosis: healthy rats (n = 6), SDZ RAD-treated healthy rats (n = 6 ), nephritic rats (n = 12), and SDZ RAD-pretreated nephritic rats (n = 12). In a separate study; 12 male Sprague-Dawley rats were analyzed in anti-Thy 1.1 nephritis: healthy rats (n = 3), nephritic rats (n = 3) and pretreated nephritic rats (n = 6). SDZ RAD and SDZ RAD placebo were given at single do ses of 2.5 mg/kg body weight per day by gavage. The experiments lasted unti l days +2 and +9 after induction of anti-Thy1.1 nephritis and until day +13 in the case of PAN nephrosis. Results: In anti-Thy1.1 nephritis, SDZ RAD d emonstrated marked proinflammatory effects in a time-dependent manner, as r eflected by severe focal damage to glomerular histology including inhibitio n of mesangial cell proliferation, reduction of creatinine clearance, and i ncrease in plasma creatinine levels as well as proteinuria. Almost identica l results were obtained in both rat strains. In contrary, SDZ RAD ameliorat ed significantly the development of PAN nephrosis. Animals pretreated by th is agent showed a significant reduction of proteinuria and of glomerular in vasion of monocytes/macrophages. Conclusion: Some caution is warranted for the use of SDZ RAD in inflammatory glomerular diseases, since it accentuate d glomerular damage induced by anti-Thy1.1 antibodies. Copyright (C) 2000 S . Karger AG, Basel.