Mechanisms Progression in Renal Insufficiency

肾病学家几乎没有预防慢性肾小球疾病进展为肾衰竭的治疗方法。这些治疗的有限疗效促使人们继续努力确定疾病进展的机制。在慢性肾小球疾病中，进展的作用与蛋白尿量密切相关。最近的研究表明，蛋白尿导致肾小管和间质损伤。这些研究的目的是为了更好地了解肾小球蛋白过滤增加对肾小管的影响机制。对这些机制的理解最终将有助于设计减缓肾脏疾病进展的治疗方法。第一个目的是评估增加的蛋白质过滤对近端小管内吞功能的影响。过滤后的蛋白质通过内吞作用进入小管细胞。然而，尚未在蛋白尿动物中研究内吞功能。拟议的研究将采用形态测定技术，以确定肾小管是否通过增加内吞膜循环的速率来响应肾小球蛋白过滤的增加。进一步的研究将检查增加的蛋白质过滤对内吞装置的关键分子组分的影响。第二个目的是检查是否可以通过阻断过滤的蛋白质的内吞作用来限制肾小管损伤。目前，阻断内吞作用的药物疗法尚不可用。因此，将在小鼠中进行测试内吞作用在肾小管损伤中的作用的研究。肾脏疾病的发展将在最近开发的小鼠品系中进行评估，其中肾小管蛋白内吞作用已通过基因敲除减少。第三个目的是确定间质性炎症是否加重由蛋白质过滤增加引起的肾小管损伤。蛋白尿性肾病的肾小管损伤总是伴随着T细胞和巨噬细胞的间质浸润。这项研究将确定阻断趋化因子信号是否能降低肾小管损伤和间质纤维化的程度。这些研究，像那些内吞作用，将采用敲除小鼠，以评估尚未受到药理学操作的损伤的潜在介质的重要性。

Nephrologists possess few treatments to prevent chronic glomerular disease from progressing to renal failure. The limited efficacy of these treatments prompts continuing efforts to identify the mechanisms responsible for disease progression. In chronic glomerular disease, the role of progression is strongly correlated with the amount of proteinuria. Recent studies have suggested that proteinuria causes tubular and then interstitial injury. The goal of the proposed studies is to better understand the mechanisms by which increasing glomerular protein filtration effects the tubule. Understanding of these mechanisms should ultimately facilitate design of therapies to slow renal disease progression. The first aim is to assess the effect of increased protein filtration on proximal tubule endocytic function. Filtered proteins are taken up into tubule cells by endocytosis. Endocytic function, however, has not been studied in proteinuric animals. The proposed studies will employ morphometric techniques to determine whether the tubule responds to increased glomerular protein filtration by increasing the rate of endocytic membrane cycling. Additional studies will examine the effect of increased protein filtration on key molecular components of the endocytic apparatus. The second aim is to examine whether tubular injury can be limited by blocking endocytosis of filtered proteins. At present, pharmacologic therapies to block endocytosis are not available. Studies to test the contribution of endocytosis in tubular injury will therefore be carried out in mice. The development of renal disease will be assessed in recently developed mouse strains in which tubular protein endocytosis has been reduced by gene knockouts. The third aim is to determine whether interstitial inflammation exacerbates tubular injury initiated by increased protein filtration. Tubular injury in proteinuric renal disease is invariably accompanied by interstitial infiltration of T cells and macrophages. The proposed studies will determine whether blocking chemokine signals responsible for cellular infiltration reduces the extent of tubular injury and interstitial fibrosis. These studies, like those of endocytosis, will employ knockout mice to assess the importance of potential mediators of injury which are not yet subject to pharmacologic manipulation.