MECHANISMS OF PROGRESSION IN RENAL INSUFFICIENCY

描述（改编自申请人的摘要）：本发明的总体目标 建议阐明血管紧张素II（A II）和 内皮素（ET）与肾功能不全的进展。 大鼠模型 慢性肾功能不全将被使用，和微穿刺，和形态学 生物化学技术将成为主要的研究方法。 为实现这一目标，列举了四个具体目标。 具体 目的1将探讨如何肾素血管紧张素系统有助于 高血压和肾功能不全时肾小球损伤。 拟议 研究将检验肾内AII活性增加的假设， 而循环AII水平在肾消融后保持正常。 特异性目标2将确定ET对改变的肾小球疾病的贡献。 肾功能不全的功能和结构。 具体目标3将评估 AII介导的高血压和局部ET产生的相互作用， 肾功能不全 最初的研究将检验血液 用AII阻断剂减压可减少ET表达， 使ET在残余肾小球中的血流动力学作用正常化。 第四 具体目标将评估AII对肾小管间质的贡献 损伤 最近的研究表明，AII促进间质纤维化 独立于其对血压和肾小球功能的影响。 是 预计随着对AII何时以及如何做出贡献的更好理解， 肾脏疾病的进展，这将是可行的， 开AII拮抗剂治疗。

DESCRIPTION (Adapted from Applicant's Abstract): The overall goal of this proposal is to elucidate the contributions of angiotensin II (A II) and endothelin (ET) to the progression of renal insufficiency. Rat models of chronic renal insufficiency will be used, and micropuncture, and morphologic and biochemical techniques will constitute the major methodologies employed. Four Specific Aims are enumerated to accomplish this objective. Specific Aim 1 will examine how the renin-angiotensin system contributes to hypertension and glomerular injury in renal insufficiency. The proposed studies will test the hypothesis that intrarenal AII activity is increased while circulating AII levels remain normal following renal ablation. Specific Aim 2 will identify the contribution of ET to altered glomerular function and structure in renal insufficiency. Specific Aim 3 will assess the interaction of AII mediated hypertension and local ET production in renal insufficiency. Initial studies will test the hypothesis that blood pressure reduction with an AII blocker reduces ET expression and thereby normalizes the hemodynamic actions of ET in remnant glomeruli. The fourth Specific Aim will assess the contribution of AII to tubulointerstitial injury. Recent studies suggest that AII promotes interstitial fibrosis independent of its effects on blood pressure and glomerular function. It is anticipated that with a better understanding of when and how AII contributes to the progression of renal disease, it will be feasible to more rationally prescribe AII antagonist therapy.