Bonegio Ramon G B, Fuhro Robert, Wang Zhiyong, Valeri C Robert, Andry Christopher, Salant David J, Lieberthal Wilfred
Evans Biomedical Research Center, Room X530, Boston University Medical Center, 650 Albany Street, Boston, MA 02129, USA.
J Am Soc Nephrol. 2005 Jul;16(7):2063-72. doi: 10.1681/ASN.2004030180. Epub 2005 May 25.
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.
蛋白尿是慢性肾衰竭进展的一个危险因素。我们建立了一个蛋白尿相关的肾小管间质损伤模型，并用于研究雷帕霉素的治疗效果。进行了两项研究。在研究A中，给蛋白尿大鼠注射羊抗Fx1A以诱导实验性膜性肾病；对照大鼠注射正常羊血清。四周后，将各组再细分，分别接受单纯剖腹手术（双侧肾脏）、单纯肾切除术（单侧肾脏）或肾切除联合部分肾切除术（切除0.6个肾脏）。4周后评估肾功能和形态。对照大鼠从未出现蛋白尿，而抗Fx1A诱导了严重蛋白尿。蛋白尿不受肾质量减少的影响。蛋白尿大鼠出现了肾小管间质疾病，在切除0.6个肾脏的大鼠中最为严重。肾功能（肾小球滤过率）因肾质量减少而降低，在切除0.6个肾脏的蛋白尿大鼠中进一步降低。在研究B中，研究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病进展的影响。所有大鼠均注射抗Fx1A并接受肾切除术，然后分为接受雷帕霉素或赋形剂的组。在4周、8周和12周后评估基因表达、肾脏形态和肾小球滤过率。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、血小板衍生生长因子、转化生长因子-β1和I型胶原）的表达。雷帕霉素改善了赋形剂处理大鼠中存在的肾小管间质炎症和间质纤维化进展。雷帕霉素还完全抑制了代偿性肾肥大。总之，雷帕霉素改善了与慢性蛋白尿和肾质量减少相关的肾小管间质疾病。
