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: 6517486
• 负责人: Leon C Moore
• 金额: $ 22.56万
• 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 2003-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517486
• 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.

在慢性肾功能衰竭（CRF）中，肾小球硬化症（GS），微管间质纤维化和微血管损伤被认为是伤害肾脏的血管内压力升高的后果。 CRF的进展通过高血压和肾脏自动调节的丧失加速。 胰岛素样生长因子1（IGF-I）增加了肾小球滤过率，并且正在研究患有生长激素（GH）不敏感性的CRF儿童的治疗用途。 由于血清抑制性IGF-I结合蛋白的高水平，CRF的IGF-I活性较低。 我们已经在成长中的大鼠中开发了一种高血压，快速促进的CRF模型，这可能与那些最有高血压和肾功能不全的儿童（包括非裔美国人儿童）以及低出生体重和先天性低肾单位数量的儿童有关。 我们发现使用IGF-1治疗可降低血压，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可以减慢儿童CRF的进展。 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及其如何受食物摄入的影响，d）定义IGF-I治疗对成年大鼠CRF的影响。 2。检验以下假设：CRF中IGF-I的有益作用不能完全归因于其降压作用。 确定内皮素-1受体阻滞是否会降低高血压和进展CRF。 3。检验以下假设：肾脏自动调节的丧失是在CRF中血管损伤和肾小球损伤发展之前的早期事件。 4。确定IGF-I是否通过与GH共同处理损害了IGF-I对CRF进展的有益作用。 5。为了确定IGF-I急性治疗能够恢复患有CRF大鼠的自动调节能力的机制，以及CRF血管反应性异常的程度是由NO产生升高介导的。断奶后不久，大鼠将为5/6肾切除术，并在4-8周后进行了研究。 将使用多种技术，包括体外容器灌注，体内肾清除分析，组织学，免疫细胞化学和西方分析。拟议的研究将是对CRF肾脏微脉管系统的病理生理学的首次全面研究，以及慢性IGF- I治疗对成长大鼠进行性CRF的影响。 结果可能对进行性肾脏不足的儿童具有治疗意义。