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）对器官移植物存活有积极影响， 移植 然而，接受这种治疗的患者中， 免疫抑制剂产生肾毒性。 已知CsA会导致 急性肾血管收缩和肾小球滤过率降低 作为一种更慢性的肾功能不全，其特征在于 小动脉病变、肾小球硬化、间质纤维化和肾小管 萎缩 虽然其机制尚不清楚，但有证据表明， 进行性CsA肾病可能具有血管基础。 拟议 研究将检验这一承诺。 该提案的目的是，首先， 确定CsA引起血管收缩的机制;第二， 确定是否持续CsA相关的血管收缩和直接内皮 或平滑肌细胞毒性导致肾血管 反应性，包括失去自动调节，第三，以确定是否 自身调节的丧失引起肾小球和肾小球后 血液动力学加速肾小球损伤并促进 肾小管间质损害 将在离体大鼠动脉中检查血管收缩的机制。 血管和内皮细胞，其中CsA刺激或抑制 将评估内皮和平滑肌血管活性因子， 完整大鼠，其中将确定肾肾上腺素能神经的作用。 血管收缩和CsA血管毒性在血管病变中的作用 将在分离的大鼠动脉血管中检查反应性，其中CsA- 将评估依赖的促有丝分裂活性和自身调节能力。 血管反应性改变和自身调节丧失对 肾小球和肾小球后血流动力学和血管完整性将 用大鼠微穿刺研究和测量后， 肾小球毛细血管通透性 该提案的目标是发展 了解CsA血管毒性的机制和后果， 可以作为预防性治疗的基础。