CELLULAR REMODELING FOLLOWING URETERAL OBSTRUCTION

通过干扰肾脏的生长和发育，先天性 尿路梗阻是最重要的原因之一 婴儿和儿童肾功能衰竭的风险。梗阻性肾病是 也是成人肾功能不全的重要原因。这个 在这项提议中要检验的中心假设是慢性 单侧输尿管梗阻诱导表型 肾小管上皮(RTE)细胞的转化导致 肾小管萎缩和间质纤维化的发展。这个 表型变化包括生长因子表达的变化， 极性丧失，间充质标志物表达，以及 从基底膜脱落。RTE细胞的细胞凋亡 显著增加导致肾小管萎缩，而 间质成纤维细胞经历增殖和肌成纤维细胞 转化，导致进行性间质纤维化。这个 第二个假设是，这些事件是由 梗阻时肾脏的发育阶段。在 建议的研究计划，mRNA定量，原位杂交， 并将使用免疫组织化学技术来研究 新生儿和新生儿肾细胞对UUO的反应(及其释放) 成年大鼠。控制肾间质异质性，单个 肾单位也会被微穿刺术所阻挡。RTE信元 将测量微丝和生长因子的产量，以及 表皮生长因子与整合素受体分布 将会被确定。细胞外基质成分和 间质纤维化的介质也将被检查。因素 调节RTE细胞表型和凋亡的研究将被研究， 包括对外源性EGF、胰岛素样生长的反应 因子-1、维甲酸和抗氧化剂：这些化合物是 可能会减少对肾脏的损伤，加速康复。通过 阐明RTE细胞调节细胞周期的机制 对UUO的回应，拟议的研究可能会导致新的 防止患者肾功能不全进展的干预措施 患有梗阻性肾病。

By interfering with renal growth and development, congenital urinary tract obstruction constitutes on of the most important causes of renal failure in infants and children. Obstructive nephropathy is also a significant cause of renal insufficiency in the adult. The central hypothesis to be tested in this proposal is that chronic unilateral ureteral obstruction (UUO) induces phenotypic transformation in renal tubular epithelial (RTE) cells that leads to the development of tubular atrophy and interstitial fibrosis. The phenotypic changes include altered expression of growth factors, loss of polarity, expression of mesenchymal markers, and detachment from the basement membrane. Apoptosis of RTE cells is markedly increased contributing to tubular atrophy, while interstitial fibroblasts undergo proliferation and myofibroblast transformation, leading to progressive interstitial fibrosis. The secondary hypothesis is that these events are modulated by the developmental stage of the kidney at the time of obstruction. In the proposed research plan, mRNA quantitation, in situ hybridization, and immonohistochemical techniques will be used to investigate the renal cellular response to UUO (and its release) in the neonatal and adult rat. To control for internephron heterogeneity, single nephrons will also be obstructed by micropuncture. RTE cell microfilament and growth factor production will be measured, and epidermal growth factor (EGF) and integrin receptor distribution will be determined. Components of extracellular matrix and mediators of interstitial fibrosis will also be examined. Factors regulating the RTE cell phenotype and apoptosis will be studied, including the response to exogenous EGF, insulin-like growth factor-1, retinoic acid, and antioxidant agents: these compounds are likely to reduce renal injury and accelerate recovery. By elucidating the mechanisms by which the RTE cell regulates the responses to UUO, the proposed studies may lead to new interventions to avert progression of renal insufficiency in patients with obstructive nephropathy.