Daniel C, Ziswiler R, Frey B, Pfister M, Marti H P
Division of Nephrology and Hypertension, Department of Medicine, Inselspital, Bern, Switzerland.
Exp Nephrol. 2000 Jan-Feb;8(1):52-62. doi: 10.1159/000020648.
BACKGROUND/AIM: The new immunosuppressant SDZ RAD, a rapamycin derivative, inhibits growth factor driven cell proliferation. SDZ RAD designed for transplantation may also be a candidate agent to treat inflammatory kidney diseases. Therefore, we investigated the effects of SDZ RAD in two different animal models of glomerulonephritis, in anti- Thy1.1 nephritis and in acute puromycin aminonucleoside (PAN) nephrosis.
Eighty-seven male Wistar rats were investigated. Anti-Thy1.1 nephritis: healthy rats (n = 9), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 9), SDZ RAD placebo treated 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 rats. 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-Thy1.1 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 doses of 2.5 mg/kg body weight per day by gavage. The experiments lasted until days +2 and +9 after induction of anti-Thy1. 1 nephritis and until day +13 in the case of PAN nephrosis.
In anti-Thy1.1 nephritis, SDZ RAD demonstrated marked proinflammatory effects in a time-dependent manner, as reflected by severe focal damage to glomerular histology including inhibition of mesangial cell proliferation, reduction of creatinine clearance, and increase in plasma creatinine levels as well as proteinuria. Almost identical results were obtained in both rat strains. In contrary, SDZ RAD ameliorated significantly the development of PAN nephrosis. Animals pretreated by this agent showed a significant reduction of proteinuria and of glomerular invasion of monocytes/macrophages.
Some caution is warranted for the use of SDZ RAD in inflammatory glomerular diseases, since it accentuated glomerular damage induced by anti-Thy1.1 antibodies.
背景/目的：新型免疫抑制剂SDZ RAD是一种雷帕霉素衍生物，可抑制生长因子驱动的细胞增殖。专为移植设计的SDZ RAD也可能是治疗炎症性肾脏疾病的候选药物。因此，我们在两种不同的肾小球肾炎动物模型（抗Thy1.1肾炎和急性嘌呤霉素氨基核苷（PAN）肾病）中研究了SDZ RAD的作用。
对87只雄性Wistar大鼠进行了研究。抗Thy1.1肾炎：健康大鼠（n = 9）、接受SDZ RAD治疗的健康大鼠（n = 6）、肾炎大鼠（n = 9）、接受SDZ RAD安慰剂治疗的肾炎大鼠（n = 6）、接受SDZ RAD预处理的肾炎大鼠（n = 9），以及早期（n = 6）和延迟（n = 6）接受SDZ RAD治疗的肾炎大鼠。PAN肾病：健康大鼠（n = 6）、接受SDZ RAD治疗的健康大鼠（n = 6）、肾炎大鼠（n = 12），以及接受SDZ RAD预处理的肾炎大鼠（n = 12）。在另一项研究中，对12只雄性Sprague-Dawley大鼠进行了抗Thy1.1肾炎分析：健康大鼠（n = 3）、肾炎大鼠（n = 3）和预处理的肾炎大鼠（n = 6）。通过灌胃给予SDZ RAD和SDZ RAD安慰剂，单剂量为每天2.5 mg/kg体重。实验持续至抗Thy1.1肾炎诱导后第2天和第9天，PAN肾病则持续至第13天。
在抗Thy1.1肾炎中，SDZ RAD呈现出明显的促炎作用，且具有时间依赖性，表现为肾小球组织学严重局灶性损伤，包括抑制系膜细胞增殖、降低肌酐清除率、升高血浆肌酐水平以及蛋白尿增加。在两种大鼠品系中均获得了几乎相同的结果。相反，SDZ RAD显著改善了PAN肾病的发展。用该药物预处理的动物蛋白尿和单核细胞/巨噬细胞的肾小球浸润明显减少。
在炎症性肾小球疾病中使用SDZ RAD时应谨慎，因为它会加重抗Thy1.1抗体诱导的肾小球损伤。
