MECHANISMS OF CYCLOSPORINE NEPHROTOXICITY

长期的目标是阐明负责 环孢素诱导的早期功能异常 肾毒性(CIN)。具体目标是： 1.为了确定肾脏血管活性激素(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 系统调节滤过率(GFR)和肾血流量的减少 (RBF)CIN的特征。 2.测定肾小球毛细血管超滤 在CIN中，系数(KF)减小。 早期CIN大鼠模型的功能和组织形态研究 将使用与人类相似的特征。测量结果将 在清醒的、长期使用环孢素A治疗的每日GRF动物中 血液和尿液中菊糖清除和修复活性激素活性。 另外，用间隙法测量GFR，用电磁场流法测量RBF 将探头制成麻醉对照，并给予环孢素急性治疗 大鼠在急性药物阻断血管紧张素II之前和之后， 肾脏激动素和输注沙拉菌素的肾脏前列腺素， 消炎痛或抑肽酶。感同身受的人的贡献 该系统还将通过急性肾去神经研究进行评估。GFR和 RBF也将在同时接受环孢素治疗的大鼠身上进行研究 和一种特定的阻滞剂，为期7天。肾小球的决定因素 超滤将使用标准的微穿孔方法进行测量 慢性CIN模型。静液压力将以 近端小管和传出小动脉，以及停流 尼弗农。全身性肾单位滤过率和蛋白质浓度 将测量传出小动脉血浆；小动脉阻力和 KF将被推导出来。这个项目的结果将阐明 CIN早期功能异常的机制。这 信息可以为有效的设计提供科学依据 治疗和预防这一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.