IGF-I AND PROGRESSION OF CHRONIC RENAL FAILURE IN RATS

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力升高损伤肾脏的后果。高血压和肾自身调节功能丧失加速了CRF的进展。 胰岛素样生长因子-1（IGF-I）可增加肾小球滤过率，目前正在研究其在伴有生长激素（GH）不敏感的CRF儿童中的治疗用途。 由于血清中抑制性IGF-I结合蛋白水平较高，CRF中IGF-I活性较低。 我们在生长期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（包括非裔美国儿童）以及低出生体重和先天性低肾单位数儿童的肾功能衰竭有关。 我们发现，IGF-I治疗可降低血压，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可减缓儿童CRF的进展。 具体目标是：1. 为了进一步表征我们的幼龄大鼠CRF模型和IGF-I治疗的影响，通过a）进行IGF-I治疗对CRF进展的影响的长期（8周）研究，B）检查IGF-I治疗在患有已建立的进展性CRF的幼龄大鼠中的影响，c）确定未治疗和IGF-I治疗的患有CRF的生长大鼠中的残余肾功能以及其如何受到食物摄入的影响，和d）确定IGF-1治疗在患有CRF的成年大鼠中的作用。 2. 验证IGF-1对CRF的有益作用不能完全归因于其降压作用的假设。 确定内皮素-1受体阻断剂是否能降低高血压和CRF进展。3. 为了验证这一假设，即肾自动调节的丧失是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联合治疗而受损。5.确定IGF-I急性治疗能够恢复生长期CRF大鼠自身调节能力的机制，以及CRF血管反应性异常由NO产生升高介导的程度。大鼠在断奶后不久将被切除5/6肾，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Western分析。拟议的研究将是第一个全面的，直接调查的病理生理学的肾微血管在CRF，慢性IGF- I治疗的影响，对进展性CRF在生长的大鼠。 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。

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.