IGF-I AND PROGRESSION OF CHRONIC RENAL FAILURE IN RATS

IGF-I 与大鼠慢性肾衰竭的进展

• 批准号: 6381172
• 负责人: Leon C Moore
• 金额: $ 21.9万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381172
• 关键词: age difference; chronic renal failure; clearance rate; eating; endothelin; growth /development; hormone receptor; hormone therapy; hypertension; immunocytochemistry; insulinlike growth factor; isolation perfusion; kidney disorder chemotherapy; laboratory rat; nephrectomy; nonhuman therapy evaluation; pathologic process; somatotropin; vasomotion; western blottings

In chronic renal failure (CRF), glomerular sclerosis (GS), tubulointerstitial fibrosis, and microvascular injury are thought to be consequences of elevated intravascular pressures that injure the kidney. The progression of CRF is accelerated by hypertension and loss of renal autoregulation. Insulin-like growth factor-1 (IGF-I) increases glomerular filtration rate, and is under investigation for therapeutic use in children with CRF with growth hormone (GH) insensitivity. IGF-I activity is low in CRF owing to high serum levels of inhibitory IGF-I binding proteins. We have developed a hypertensive, rapidly-progressing model of CRF in growing rats that may be relevant to renal failure in those children most at risk for hypertension and renal insufficiency, including African-American children, and those with low birth weight and congenital low nephron number. We found that treatment with IGF-I lowers blood pressure, preserves renal function, reduces the severity of GS, and completely prevents vascular injury, suggesting that IGF-I could slow the progression of CRF in children. The specific aims are: 1. To further characterize our model of CRF in young rats and the impact of IGF-I therapy by a) conducting longer-term (8 week) studies of the effect of IGF-I therapy on the progression of CRF, b) examining the effects of IGF-I therapy in young rats with established progressive CRF, c) to define residual renal function in untreated and IGF-I treated growing rats with CRF and how this is influenced by food intake, and d) defining the effects of IGF-I therapy in adult rats with CRF. 2. To test the hypothesis that the beneficial effects of IGF-I in CRF can not be fully attributed to its antihypertensive action. To determine if endothelin-1 receptor blockade reduces hypertension and progression CRF. 3. To test the hypothesis that the loss of renal autoregulation is an early event that precedes the development of both vascular injury and glomerular injury in CRF. 4. To determine if the beneficial effects of IGF-I on the progression of CRF are compromised by co-treatment with GH. 5. To identify the mechanisms through which acute treatment with IGF-I is able to restore autoregulatory ability in growing rats with CRF, and the extent to which abnormalities in vascular reactivity in CRF are mediated by elevated NO production. Rats will be 5/6 nephrectomized shortly after weaning, and studied 4-8 weeks later. A variety of techniques will be used, including vessel perfusion in vitro, renal clearance analysis in vivo, and histological, immunocytochemical, and Western analyses. The proposed studies will be the first comprehensive, direct investigations of the pathophysiology of the renal microvasculature in CRF, and of the effects of chronic IGF- I therapy on progressive CRF in growing rats. The results may have therapeutic implications for children with progressive renal insufficiency.

在慢性肾衰竭（CRF）中，肾小球硬化（GS）、肾小管间质纤维化和微血管损伤被认为是血管内压升高损伤肾脏的结果。高血压和肾脏自动调节功能丧失会加速 CRF 的进展。 胰岛素样生长因子-1 (IGF-I) 可增加肾小球滤过率，目前正在研究用于治疗生长激素 (GH) 不敏感的 CRF 儿童。 由于抑制性 IGF-I 结合蛋白的血清水平较高，CRF 中 IGF-I 活性较低。 我们在生长大鼠中开发了一种高血压、快速进展的 CRF 模型，该模型可能与那些最有高血压和肾功能不全风险的儿童的肾功能衰竭有关，包括非洲裔美国儿童以及低出生体重和先天性低肾单位数量的儿童。 我们发现，IGF-I 治疗可以降低血压，保留肾功能，降低 GS 的严重程度，并完全防止血管损伤，这表明 IGF-I 可以减缓儿童 CRF 的进展。 具体目标是： 1. 进一步表征我们的幼年大鼠 CRF 模型以及 IGF-I 治疗的影响，方法是：a) 对 IGF-I 治疗对 CRF 进展的影响进行长期（8 周）研究，b) 检查 IGF-I 治疗对已确定进展性 CRF 的幼年大鼠的影响，c) 确定未治疗和 IGF-I 治疗的生长大鼠的残余肾功能 CRF 及其如何受食物摄入的影响，以及 d) 定义 IGF-I 治疗对成年 CRF 大鼠的影响。 2.检验IGF-I对CRF的有益作用不能完全归因于其抗高血压作用的假设。 确定内皮素 1 受体阻断是否会降低高血压和 CRF 进展。 3. 检验以下假设：肾自动调节功能丧失是 CRF 中血管损伤和肾小球损伤发生之前的早期事件。 4. 确定 IGF-I 对 CRF 进展的有益作用是否因与 GH 联合治疗而受到损害。 5. 确定IGF-I急性治疗能够恢复患有CRF的生长大鼠的自身调节能力的机制，以及CRF中血管反应性异常在多大程度上是由NO产生升高介导的。断奶后不久将对大鼠进行5/6肾切除，并在4-8周后进行研究。 将使用多种技术，包括体外血管灌注、体内肾清除率分析以及组织学、免疫细胞化学和蛋白质印迹分析。拟议的研究将是首次全面、直接研究 CRF 肾微血管的病理生理学，以及慢性 IGF-I 治疗对生长大鼠进行性 CRF 的影响。 该结果可能对患有进行性肾功能不全的儿童具有治疗意义。