MECHANISMS OF PROGRESSION IN RENAL INSUFFICIENCY

描述(改编自申请者摘要)：本报告的总体目标 建议阐明血管紧张素II(A II)和 内皮素(ET)与肾功能不全进展的关系Wistar大鼠模型 慢性肾功能不全将采用显微穿刺术，并对其进行形态学观察 而生化技术将构成所采用的主要方法。 为实现这一目标，列举了四个具体目标。特定的 目标1将研究肾素-血管紧张素系统如何在 肾功能不全时的高血压和肾小球损伤。建议数 研究将检验肾内AII活性增加的假设 而循环中的AII水平在肾脏消融后仍保持正常。 特定目标2将确定ET在肾小球病变中的作用 肾功能不全的功能和结构。特定目标3将评估 血管紧张素Ⅱ介导的高血压与局部ET产生的相互作用 肾功能不全。初步研究将检验血液的假设 AII受体阻滞剂降压可降低ET的表达，从而 使残留肾小球内ET的血流动力学作用正常化。第四次 特定的目的将评估ALII对肾小管间质的贡献 受伤。最近的研究表明，AII促进间质纤维化 与其对血压和肾小球功能的影响无关。它是 预计在更好地理解AII何时以及如何做出贡献的情况下 对于肾脏疾病的进展，更合理地进行 开出所有的拮抗剂疗法。

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.