Investigation of pathogenesis and progression of interstitial disorder mediated by FcRn in glomerulonephritis.

在肾脏中，通过肾小球滤过的蛋白质通过内吞作用沿近端小管沿着重吸收，以避免肾脏丢失大量蛋白质，如白蛋白、β_2-微球蛋白和几种激素。虽然白蛋白的重吸收可以防止这种主要血浆蛋白通过尿液大量丢失，但白蛋白的过度重吸收可能是慢性肾脏疾病发生和进展的一个因素。因此，肾脏似乎对蛋白质的量有限制，蛋白质可以在肾脏疾病中发现的大大增加的滤过负荷下被重吸收和分解代谢。另一方面，免疫球蛋白如IgG、伊加及其片段也已在尿中发现。与其他蛋白质类似，这些分子的吸收似乎受到近端小管中的内吞途径的调节，但其机制尚未完全了解。最近的一项研究表明，新生儿Fc受体（FcRn）参与IgG a的转运， ...更多信息 跨上皮和内皮细胞，表达于近端肾小管上皮细胞。提示FcRn在肾小管液IgG重吸收中可能起重要作用。然而，到目前为止，没有直接证据表明受体介导的IgG内吞作用在人类肾近端肾小管上皮细胞中。为了探索FcRn在近端小管中的生理作用，我们使用人肾近端小管上皮细胞（RPTECs）检测IgG转运。FcRn在RPTECs中表达，并与β_2-微球蛋白结合，保留了特异性pH依赖性IgG结合的能力。人IgG转运试验表明，受体介导的完整IgG在RPTEC中的跨上皮转运是双向的，并且它需要形成酸化的细胞内隔室。使用双重免疫荧光，内化的人IgG显示在RPTEC的细胞质中标记并与FcRn共定位。这些数据定义了RPTEC单层中FcRn相关IgG转运的机制。少

In the kidney, proteins filtered through glomeruli are reabsorbed by endocytosis along the proximal tubules to avoid renal loss of large amounts of proteins such as albumin, β_2-microglobulin and several hormones. Although the reabsorption of albumin prevents the loss of large amounts of this major plasma protein via the urine, excess reabsorption of albumin may be a factor for the development and progression of chronic renal diseases. Thus, the kidney appears to have a limit on the amount of protein which can be reabsorbed and catabolized at the greatly increased filtered-loads found in renal diseases. On the other hand, immunoglobulins such as IgG, IgA, and their fragments have also been found in the urine. Similar to other proteins, absorption of these molecules seems to be regulated by the endocytosis pathway in the proximal tubules, but the mechanisms are not fully understood. A recent study revealed that the neonatal Fc receptor (FcRn), which is involved in the transport of IgG a … More cross several epithelial and endothelial cells, was expressed in renal proximal tubular epithelial cells. It was suggested that FcRn may play an important role in the reabsorption of IgG from the tubular fluid. However, to date there is no direct evidence for receptor-mediated endocytosis of IgG in the renal proximal tubular epithelial cells in humans. To explore the physiological roles of FcRn in the proximal tubules, we examined IgG transport using human renal proximal tubular epithelial cells (RPTECs). FcRn was expressed in RPTECs and physically associated with β_2-microglobulin, preserving the capacity of specific pH-dependent IgG binding Human IgG was bound to the cell surface of RPTECs in a pH-dependent manner. The human IgG transport assay revealed that receptor-mediated transepithelial transport of intact IgG in RPTECs was bidirectional and that it requires the formation of acidified intracellular compartments. Using double immunofluorescence, internalized human IgG was shown to be marked in cytoplasm of RPTECs and colocalized with FcRn. There data define the mechanisms of FcRn-associated IgG transport in the RPTEC monolayers. Less