Young B A, Burdmann E A, Johnson R J, Andoh T, Bennett W M, Couser W G, Alpers C E
Department of Medicine, University of Washington, Seattle, USA.
Kidney Int. 1995 Aug;48(2):431-8. doi: 10.1038/ki.1995.311.
Chronic cyclosporine (CsA) nephrotoxicity is a major complication of heart, bone marrow, and renal transplantation, and is characterized in humans by striped interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of hilar arterioles. This last feature is highly specific for cyclosporine injury and has been difficult to reproduce in normotensive animal models. Salt-depletion has been shown to sensitize rodents to the effects of CsA and accelerate the disease process. We conducted sequential studies in chronically salt depleted, pair fed rats treated with CsA (15 mg/kg, s.c.) or an equivalent dose of olive oil vehicle, and found a histologic lesion associated with CsA that consisted of striped cortical interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of many afferent arterioles. The arteriolopathy was first detected at day 10 with progressive hyalinization of arterioles continuing until termination of the study at day 35. The arteriolopathy consisted initially of eosinophilic granular transformation of smooth muscle cells comprising afferent hilar glomerular arterioles, and progressed to foci of smooth muscle cell vacuolization and accumulation of discrete hyaline deposits in vessel walls. Electron microscopy demonstrated marked accumulation of typical renin granules throughout the smooth muscle cell cytoplasm, corresponding to the eosinophilic granular transformation revealed histologically. Immunocytochemistry confirmed the up-regulated production of renin in these vessels. This study documents a rodent model for CsA arteriolopathy and CsA-associated interstitial fibrosis that strikingly reproduces the most characteristic nephropathic effects of cyclosporine found in human patients treated with this agent.(ABSTRACT TRUNCATED AT 250 WORDS)
慢性环孢素（CsA）肾毒性是心脏、骨髓和肾移植的主要并发症，在人类中其特征为条纹状间质纤维化、肾小管扩张和萎缩以及肾门小动脉玻璃样变。最后这一特征对环孢素损伤具有高度特异性，且难以在正常血压动物模型中重现。已表明盐耗竭会使啮齿动物对CsA的作用敏感并加速疾病进程。我们对长期盐耗竭、配对饲养并用CsA（15mg/kg，皮下注射）或等量橄榄油载体处理的大鼠进行了系列研究，发现与CsA相关的一种组织学病变，包括条纹状皮质间质纤维化、肾小管扩张和萎缩以及许多入球小动脉玻璃样变。小动脉病变在第10天首次检测到，小动脉逐渐玻璃样变持续至研究第35天结束。小动脉病变最初表现为构成肾门入球小动脉的平滑肌细胞嗜酸性颗粒样转化，并进展为平滑肌细胞空泡化灶以及血管壁离散透明沉积物的积聚。电子显微镜显示典型肾素颗粒在整个平滑肌细胞质中显著积聚，与组织学显示的嗜酸性颗粒样转化一致。免疫细胞化学证实这些血管中肾素产生上调。本研究记录了一种用于CsA小动脉病变和CsA相关间质纤维化的啮齿动物模型，该模型惊人地重现了接受此药治疗的人类患者中发现的环孢素最具特征性的肾病效应。（摘要截短于250字）
