IGF-I AND PROGRESSION OF CHRONIC RENAL FAILURE IN RATS

在慢性肾衰竭（CRF）中，肾小球硬化（GS）、小管间质纤维化和微血管损伤被认为是血管内压力升高损伤肾脏的后果。慢性肾功能衰竭的进展可因高血压和肾脏自身调节功能丧失而加速。胰岛素样生长因子-1 （igf -1）增加肾小球滤过率，并正在研究用于治疗儿童慢性肾功能衰竭与生长激素（GH）不敏感。由于抑制igf - 1结合蛋白的高血清水平，CRF中igf - 1活性较低。我们在生长大鼠中建立了一种高血压、快速进展的CRF模型，该模型可能与高血压和肾功能不全风险最高的儿童肾功能衰竭有关，包括非裔美国儿童、低出生体重和先天性低肾单位数的儿童。我们发现使用IGF-I治疗可以降低血压，保持肾功能，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。进一步描述我们的模型CRF的年轻老鼠和IGF-I疗法的)进行长期的影响(8周)的影响的研究IGF-I治疗CRF的进展,b)检查IGF-I疗法的影响在年轻大鼠建立了进步CRF, c)来定义残余肾功能治疗在治疗和IGF-I增长与CRF大鼠以及这是如何受到食物摄入量的影响,和d)定义与CRF IGF-I治疗成年老鼠的影响。2. 为了验证igf - 1在CRF中的有益作用不能完全归因于其降压作用的假设。目的：确定内皮素-1受体阻断是否能降低高血压和慢性肾功能衰竭的进展。3. 为了验证肾自身调节功能丧失是CRF中血管损伤和肾小球损伤发生之前的早期事件这一假设。4. 确定igf - 1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CRF生长大鼠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一氧化氮生成升高介导的。大鼠将在断奶后不久进行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、组织学、免疫细胞化学和Western分析。该研究将首次全面、直接地研究肾微血管在CRF中的病理生理学，以及慢性IGF- I治疗对生长大鼠进行性CRF的影响。该结果可能对进行性肾功能不全的儿童具有治疗意义。

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.