MECHANISMS OF VASOTOXICITY AS PREVENTION OF CYCLOSPORINE NEPHROTOXICITY

血管毒性预防环孢素肾毒性的机制

• 批准号: 3776408
• 负责人: JOHN D CONGER
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3776408
• 关键词: acute renal failure; cyclosporines; drug adverse effect; kidney circulation; laboratory rat; micropuncture; perfusion; renal glomerulus; renal ischemia /hypoxia; vascular endothelium; vascular endothelium permeability; vascular smooth muscle; vascular smooth muscle nervous control; vasoconstriction

Cyclosporine (CsA) has had a positive impact on graft survival in organ transplantation. However, a significant percent of patients receiving this immunosuppressive agent develop nephrotoxicity. CsA is known to cause acute renal vasoconstriction and reduction in glomerular filtration as well as a more chronic form of renal dysfunction characterized by arteriolopathy, glomerulosclerosis, interstitial fibrosis and tubular atrophy. While the mechanism is not understood, evidence suggests that progressive CsA nephropathy may have a vascular basis. The proposed studies will examine this promise. The purpose of the proposal is, first, to determine the mechanism of CsA-induced vasoconstriction; second, to determine if continuous CsA-related vasoconstriction and direct endothelial or smooth muscle cell toxicity leads to fixed alterations in renovascular reactivity including loss of autoregulation, and third, to determine if the loss of autoregulation causes changes in glomerular and post-glomerular hemodynamics that accelerate glomerular-injury and promote tubulointerstitial damage. The mechanism of vasoconstriction will be examined in isolated rat arterial vessels and endothelial cells in which CsA stimulation or suppression of endothelial and smooth muscle vasoactive factors will be assessed and in intact rats where the role of renal adrenergic nerves will be determined. The role of vasoconstriction and CsA vasotoxicity in altered vascular reactivity will be examined in isolated rat arterial vessels in which CsA- dependent mitogenic activity and autoregulatory capacity will be assessed. The effect of altered vascular reactivity and loss of autoregulation on glomerular and post-glomerular hemodynamics and vascular integrity will be determined with rat micropuncture studies and measurements of post- glomerular capillary permeability. The goal of this proposal is to develop an understanding of the mechanism and consequences of CsA vasotoxicity that can serve as a basis for preventive therapy.

环孢素（CSA）对器官的移植生存有积极影响 移植。 但是，接受此此事的患者中有很大一部分 免疫抑制剂会发展出肾毒性。 众所周知CSA会导致 急性肾血管收缩和肾小球滤过还原 作为一种更慢性的肾功能障碍，其特征是 小动脉病，肾小球硬化，间质性纤维化和管状 萎缩。 虽然该机制尚不理解，但有证据表明 进行性CSA肾病可能具有血管基础。 提议 研究将研究这一诺言。 该提议的目的是 确定CSA诱导的血管收缩的机制；第二，到 确定连续与CSA相关的血管收缩和直接内皮 或平滑肌细胞毒性会导致肾脏固定改变 反应性，包括自动调节的丧失，第三，以确定是否是否 自动调节的损失会导致肾小球和胶合后的变化 加速肾小球伤害并促进的血液动力学 Tubulointerstitial损害。 血管收缩的机制将在孤立的大鼠动脉中检查 血管和内皮细胞中CSA刺激或抑制 将评估内皮和平滑肌血管活性因子，并在 完整的大鼠将确定肾脏肾上腺素能神经的作用。 血管收缩和CSA血管毒性在变化的血管中的作用 将在分离的大鼠动脉血管中检查反应性，其中CSA- 将评估依赖性有丝分裂活性和自动调节能力。 血管反应性改变和自动调节损失的影响 肾小球和肾小球后血液动力学和血管完整性将是 通过大鼠微攻击研究确定和测量 肾小球毛细管渗透性。 该提议的目的是发展 了解CSA血管毒性的机制和后果 可以作为预防治疗的基础。