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功能衰竭的治疗方法。这些疗法的疗效有限，促使人们继续努力确定导致疾病进展的机制。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，蛋白尿会导致肾小管损伤，进而导致间质损伤。拟议研究的目的是更好地了解增加肾小球蛋白滤过率影响肾小管的机制。对这些机制的了解最终应该有助于设计延缓肾脏疾病进展的治疗方法。第一个目的是评估增加蛋白质过滤对近端小管内皮细胞功能的影响。过滤后的蛋白质通过内吞作用进入肾小管细胞。然而，蛋白尿动物的内吞功能还没有被研究过。拟议的研究将使用形态计量学技术来确定肾小管是否通过增加内细胞膜的循环率来响应增加的肾小球蛋白过滤。更多的研究将检验增加的蛋白质过滤对内吞细胞器的关键分子成分的影响。第二个目的是研究是否可以通过阻断过滤蛋白的内吞作用来限制肾小管损伤。目前，还没有阻断内吞作用的药物疗法。因此，将在小鼠身上进行研究，以测试内吞作用在肾小管损伤中的作用。肾脏疾病的发展将在最近开发的小鼠品系中进行评估，在这些品系中，肾小管蛋白内吞作用通过基因敲除而减少。第三个目的是确定间质炎症是否加剧了由蛋白滤过增加引起的肾小管损伤。蛋白尿肾病肾小管损伤常伴有T细胞和巨噬细胞的间质浸润。拟议中的研究将确定阻断与细胞渗透有关的趋化因子信号是否能减少肾小管损伤和间质纤维化的程度。这些研究与内吞作用的研究一样，将使用基因敲除小鼠来评估潜在的损伤介质的重要性，这些介质尚未受到药物操纵的影响。

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.