IGF-I AND PROGRESSION OF CHRONIC RENAL FAILURE IN RATS

在慢性肾功能衰竭(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损伤肾脏的血管内压升高的后果。高血压和肾脏自动调节功能丧失加速了CRF的进展。胰岛素样生长因子-1(IGF-I)增加肾小球滤过率，正在研究用于生长激素(GH)不敏感的CRF儿童的治疗。慢性肾功能衰竭患者的IGF-I活性较低，原因是血清中抑制性IGF-I结合蛋白水平较高。我们在生长中的大鼠中建立了一种快速进展的高血压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的肾衰竭有关，包括非裔美国儿童，以及低出生体重和先天性低肾单位数量的儿童。我们发现，使用IGF-I治疗可以降低血压，保护肾功能，减轻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。具体目的是：1.通过a)对IGF-I治疗对CRF进展的影响进行长期(8周)研究，b)检测IGF-I治疗对已建立的进展性CRF的年轻大鼠的影响，c)确定未治疗和IGF-I治疗的CRF生长期大鼠的残余肾功能以及食物摄入量对其的影响，以进一步表征我们的CRF幼鼠模型和IGF-I治疗的影响，以及d)确定IGF-I治疗对成年CRF大鼠的影响。2.验证IGF-I对CRF的有益作用不能完全归因于其降压作用的假设。目的：确定阻断内皮素-1受体是否能降低高血压和慢性肾功能衰竭的进展。3.验证肾自动调节功能丧失是CRF血管损伤和肾小球损伤发生的早期事件的假说。4.探讨胰岛素样生长因子-I(IGF-I)对慢性肾功能衰竭(CRF)进展的有益影响是否被GH联合治疗所影响。5.明确IGF-I急性治疗能够恢复生长期CRF大鼠的自我调节能力的机制，以及CRF血管反应性异常在多大程度上是由NO产生增加所介导的。断乳后不久将大鼠5/6肾切除，4-8周后进行研究。将使用各种技术，包括体外血管灌流，体内肾脏清除量分析，以及组织学、免疫细胞化学和Western分析。这项拟议的研究将是首次全面、直接地研究CRF肾微血管的病理生理学，以及慢性IGF-I治疗对生长期大鼠进展性CRF的影响。这一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.