Department of Pathology, Louisiana State University Health, Shreveport, Louisiana, USA.
Kidney Int. 2014 Oct;86(4):738-46. doi: 10.1038/ki.2014.122. Epub 2014 Apr 30.
In vitro and ex vivo studies have elucidated the step-by-step process whereby some physicochemically abnormal light chains are processed by mesangial cells to form amyloid fibrils. Although crucial steps in the cascade of events have been determined, these findings have not been reproduced in vivo. This has led to some doubts as to the significance and clinical application of the information that has been deciphered. Here, we developed an animal model which uses mice injected with amyloidogenic light chains purified from the urine of patients with biopsy-proven, light-chain-associated glomerular amyloidosis which validated in vitro/ex vivo findings. This animal model showed internalization of the light chains utilizing caveolae followed by trafficking to the mature lysosomal compartment where fibrils were formed. This model permits evaluation of mesangial amyloidogenesis for prolonged periods of time, is potentially useful to test maneuvers to modulate events that take place, and can be used to design novel therapeutic interventions.
体外和体内研究阐明了某些物理化学异常轻链被肾小球系膜细胞加工形成淀粉样纤维的逐步过程。尽管已经确定了事件级联中的关键步骤，但这些发现尚未在体内重现。这导致人们对已破译信息的意义和临床应用产生了一些怀疑。在这里，我们开发了一种动物模型，该模型使用从小鼠尿液中纯化的淀粉样变性轻链注射到经活检证实的、与轻链相关的肾小球淀粉样变性患者，验证了体外/体内的发现。该动物模型显示了轻链的内化，利用小窝内陷，然后转运到成熟的溶酶体区室，在那里形成纤维。该模型允许对系膜淀粉样变性进行长时间的评估，对于测试调节发生的事件的操作具有潜在的用途，并且可以用于设计新的治疗干预措施。
