雷帕霉素加重蛋白负荷肾病大鼠肾脏的损害及氯沙坦的保护作用

目的 观察雷帕霉素对蛋白负荷肾病大鼠肾脏组织和肾功能的影响及氯沙坦的保护作用，并探讨相关机制。 方法 采用牛血清蛋白（BSA）诱导Wistar雌性大鼠建立蛋白负荷的肾病大鼠模型，根据处理不同分成模型对照组、雷帕霉素组（单纯使用雷帕霉素，Rapa组）和氯沙坦组（同时使用雷帕霉素和氯沙坦）。检测不同时间点各组大鼠的尿蛋白量（24 h）和肾功能水平，并对肾组织进行光镜和电镜检查。 结果 实验第7 天，Rapa组和氯沙坦组大鼠尿蛋白量（24 h）均显著高于模型组（均P < 0.05），但氯沙坦组大鼠尿蛋白量（24 h）较Rapa组有明显缓解（P < 0.05）。实验第14天，Rapa组大鼠尿蛋白量（24 h）仍显著高于模型组（P <0.05），而氯沙坦组与模型对照组间的尿蛋白量（24 h）差异已无统计学意义。肾组织光镜检查显示Rapa组大鼠肾小管管腔中的蛋白管型明显增加；而氯沙坦组的蛋白尿和蛋白管型较Rapa组有明显减少；电镜结果显示Rapa组肾脏可见明显的肾小球局灶性足突融合。 结论 雷帕霉素增加蛋白负荷肾病大鼠的蛋白尿水平，其主要机制可能与雷帕霉素损伤肾小球足细胞后导致肾小球滤过屏障的改变有关；氯沙坦可以减轻雷帕霉素所致的大量蛋白尿。

Rapamycin aggravates the renal damage in rats with protein overload nephropathy and the protection of losartan

Objective To investigate the effects of rapamycin on renal tissue and function of rats with protein overload nephropathy and to explore the protective mechanism of losartan. Methods Experimental rat models with protein overload nephropathy, induced by intraperiotoneal injection of BSA (2. 0 g/d)into female Wistar rats, were divided into three groups: control group, rapamycin group(injected intraperitoneally with rapamycin) and losartan group(injected intraperitoneally with rapamycin and given orally with losartan). At different time points, the quantity of 24-hour urine protein and renal function were measured, and the morphologic changes of renal tissues were evaluated by HE staining and electron microscope. Results Both at day 7 and day 14, rats received BSA developed intense proteinuria. At day 7, compared with control group, 24-hour proteinuria increased markedly in rapamyein group (P<0.05). Nevertheless,proteinufia was notably alleviated in losartan group (P<0.05). At day 14, 24-hour-urine protein of rapamycin group was also significantly higher than that of the losartan group (P<0.05), but therewas no significant difference between control group and losartan group (P>0.05). Proteinuria and intratubular albumin cast formation were alleviated notably in losartan group. The fusion of focal podocytes in rapamycin group was obvious in comparison with control group. Conclusions Rapamycin can agrravate proteinuria in rats with protein overload nephropathy through changing the barrier of glomerular filtration by damaging podocytes. Furthermore, losartan can alleviate severe proteinuria induced by rapamycin.