Division of Pediatric Nephrology, Children's Hospital of Pittsburgh, 530 45th Street 5th Floor, Office # 5129, Pittsburgh, PA 15201, USA.
Pediatr Nephrol. 2013 Jul;28(7):1049-58. doi: 10.1007/s00467-012-2335-1. Epub 2012 Nov 3.
One of the major challenges of nephrology is to develop therapeutic strategies to halt the progression of kidney diseases. In clinical settings, nephrotic-range proteinuria correlates with the rate of progression, particularly in glomerular diseases. Hence, the degree of proteinuria has been utilized to monitor the response to treatment as well as to predict outcome. However, the pathophysiology of proteinuria-induced progression remains unknown. Albumin accounts for the majority of the protein in nephrotic urine and as a result of this clinical observation studies have focused on understanding the adverse effects of albumin overload in the kidney. Albumin is internalized by receptor-mediated endocytosis in proximal tubule cells via low density lipoprotein (LDL) type receptor, megalin. Albumin at high concentrations mimicking nephrotic milieu has resulted in the upregulation of pro-inflammatory/fibrogenic genes and apoptosis in proximal tubule cells in in vivo and in vitro models of albumin overload. These properties of albumin on proximal tubule cells may explain extensive tubulointerstitial fibrosis and tubular atrophy observed in end-stage kidney disease. In addition to tubular toxicity, podocytes respond to proteinuric states by cytoskeletal alterations and loss of the differentiation marker synaptopodin. Identifying the molecular network of proteins involved in albumin handling will enable us to manipulate the specific signaling pathways and prevent damage caused by proteinuria.
肾脏病学面临的主要挑战之一是开发治疗策略以阻止肾脏疾病的进展。在临床环境中，肾病范围内的蛋白尿与进展速度相关，特别是在肾小球疾病中。因此，蛋白尿的程度已被用于监测治疗反应以及预测预后。然而，蛋白尿诱导进展的病理生理学仍然未知。白蛋白占肾病尿液中蛋白质的大部分，因此，研究集中在了解白蛋白过载对肾脏的不良影响。白蛋白通过低密度脂蛋白 (LDL) 型受体、巨球蛋白在内皮细胞中通过受体介导的内吞作用被内化。在白蛋白过载的体内和体外模型中，模拟肾病环境的高浓度白蛋白导致近端小管细胞中促炎/纤维化基因和细胞凋亡的上调。白蛋白对近端小管细胞的这些特性可能解释了在终末期肾病中观察到的广泛的肾小管间质纤维化和肾小管萎缩。除了肾小管毒性外，足细胞还通过细胞骨架改变和分化标志物突触蛋白的丢失对蛋白尿状态做出反应。鉴定涉及白蛋白处理的蛋白质的分子网络将使我们能够操纵特定的信号通路并防止蛋白尿引起的损伤。
