IGF-I AND PROGRESSION OF CHRONIC RENAL FAILURE IN RATS

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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.