Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy
Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy
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DOI：
10.1681/asn.2004030180
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发表时间：
2005-07-01
影响因子：
13.6
通讯作者：
Lieberthal, W
中科院分区：
文献类型：
--
作者：
Bonegio, RGB;Fuhro, R;Lieberthal, W
蛋白尿是慢性肾衰竭进展的危险因素。建立了蛋白尿相关小管间质损伤模型，并用于观察雷帕霉素的治疗效果。进行了两项研究。在研究A中，蛋白尿大鼠给予羊抗fx1a诱导实验性膜性肾病；对照组大鼠注射正常羊血清。4周后，各组再细分，分别进行单独剖腹手术（2个肾）、单独肾切除术（1个肾）或肾切除术合并肾根切除术（0.6个肾）。4周后观察肾功能及形态学变化。而对照大鼠从未发生蛋白尿，抗fx1a诱导了严重的蛋白尿。蛋白尿不受肾肿块减少的影响。蛋白尿大鼠发生小管间质疾病，其中0.6肾大鼠最为严重。肾功能（GFR）随着肾团块的丢失而降低，并且在0.6肾的蛋白尿大鼠中进一步降低。在研究B中，我们检测了雷帕霉素对候选促炎和促纤维化基因表达以及蛋白尿相关肾脏疾病进展的影响。所有大鼠均接受抗fx1a注射，并切除肾脏，然后分为各组接受雷帕霉素或载药。在4、8和12周后评估基因表达、肾脏形态和GFR。雷帕霉素降低了促炎和促纤维化基因（单核细胞趋化蛋白-1、血管内皮生长因子、PDGF、tgf - β(1)和1型胶原）的表达。雷帕霉素可以改善大鼠的小管间质炎症和间质纤维化的进展。雷帕霉素也完全抑制代偿性肾肥大。总之，雷帕霉素可以改善与慢性蛋白尿和肾肿块丢失相关的小管间质疾病。
Proteinuria is a risk factor for progression of chronic renal failure. A model of proteinuria-associated tubulointerstitial injury was developed and was used to examine the therapeutic effect of rapamycin. Two studies were performed. In study A, proteinuric rats were given sheep anti-Fx1A to induce experimental membranous nephropathy; control rats received normal sheep serum. Four weeks later, groups were subdivided and underwent laparotomy alone (two kidneys), nephrectomy alone (one kidney), or nephrectomy with polectomy (0.6 kidney). Renal function and morphology were evaluated 4 wk later. Whereas control rats never developed proteinuria, anti-Fx1A induced severe proteinuria. Proteinuria was unaffected by renal mass reduction. Proteinuric rats developed tubulointerstitial disease that was most severe in rats with 0.6 kidneys. Renal function (GFR) was reduced by loss of renal mass and was reduced further in proteinuric rats with 0.6 kidneys. In study B, the effect of rapamycin on the expression of candidate proinflammatory and profibrotic genes and the progression of proteinuria-associated renal disease were examined. All rats received an injection of anti-Fx1A and were nephrectomized and then divided into groups to receive rapamycin or vehicle. Gene expression, renal morphology, and GFR were evaluated after 4, 8, and 12 wk. Rapamycin reduced expression of the proinflammatory and profibrotic genes (monocyte chemotactic protein-1, vascular endothelial growth factor, PDGF, TGF-beta(1), and type 1 collagen). Tubulointerstitial inflammation and progression of interstitial fibrosis that were present in vehicle-treated rats were ameliorated by rapamycin. Rapamycin also completely inhibited compensatory renal hypertrophy. In summary, rapamycin ameliorates the tubulointerstitial disease associated with chronic proteinuria and loss of renal mass.