MECHANISMS OF CYCLOSPORINE NEPHROTOXICITY

长期的目标是阐明负责的机制 环孢素诱导的早期功能异常 肾毒性（CIN）。 具体目标是： 1.为了确定肾血管活性激素（肾素-血管紧张素， 前列腺素和激肽释放酶-激肽系统）和/或交感神经系统 系统介导滤过率（GFR）和肾血流量降低 (RBF)CIN的特征。 2.以确定是否肾小球毛细血管超滤 系数（Kf）在CIN中减小。 早期CIN大鼠模型的建立 将使用与人类相似的特征。 测量将 在每日GRF的清醒、长期环孢霉素治疗的动物中通过 菊糖清除率和血液和尿液中的肾活性激素活性。 此外，通过间隙测量GFR，通过电磁流测量RBF 探针将在麻醉对照组和急性环孢素治疗组中进行 大鼠，在血管紧张素II急性药理学阻断之前和之后， 通过输注saralasin， 吲哚美辛或抑肽酶。 交感神经的作用 系统也将通过急性肾去神经研究进行评价。 GFR和 还将在同时接受环孢菌素治疗的大鼠中研究RBF 和一种特定的阻滞剂持续7天。 肾小球疾病的决定因素 超滤将用标准微穿刺方法测量， CIN的慢性模型。 流体静压力将在 近端小管和输出小动脉，以及在停止流 肾单位 肾单位滤过率和蛋白质浓度 和传出小动脉血浆;小动脉阻力和 Kf将被导出。 该项目的结果将阐明 导致早期CIN功能异常的机制。 这 信息可以为设计有效的 治疗和预防这种不良反应的治疗干预措施 越来越多地使用免疫抑制剂。

The long-term goal is to elucidate the mechanisms responsible for functional abnormalities present in the early phase of cyclosporine-induced nephrotoxicity (CIN). The specific aims are: 1. To determine if the renal vasoactive hormones (renin-angiotensin, prostaglandin, and kallikrein-kinin systems) and/or the sympathetic nervous system mediate the reduced rates of filtration (GFR) and renal blood flow (RBF) characteristic of CIN. 2. To determine whether the glomerular capillary ultrafiltration coefficient (Kf) is reduced in CIN. A rat model of early CIN with both functional and histomorphologic characteristics similar to those in humans will be used. Measurements will be made in awake, chronically cyclosporine treated animals of daily GRF by inulin clearance and renovasoactive hormone activities in blood and urine. Also, measurements of GFR by clearance and RBF by electromagnetic flow probe will be made in anesthetized control and acutely cyclosporine-treated rats, both before and after acute pharmacologic blockade of angiotensin II, renal kinins, and renal prostaglandins by infusions of saralasin, indomethacin or aprotinin. The contribution of the sympathetic nervous system will also be evaluated by acute renal denervation studies. GFR and RBF will also be studied in rats simultaneously treated with cyclosporine and a specific blocker for 7 days. The determinants of glomerular ultrafiltration will be measured with standard micropuncture methodology in the chronic model of CIN. Hydrostatic pressures will be measured in proximal tubules and efferent arterioles, as well as in stop-flow nephrons. Nephron filtration rates and protein concentrations in systemic and efferent arteriolar plasma will be measured; arteriolar resistances and Kf will be derived. The results of this project will elucidate the mechanisms responsible for the functional abnormalities in early CIN. This information may provide a scientific basis for the design of effective therapeutic interventions to treat and prevent the adverse effects of this increasingly utilized immunosuppressant.