The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney.
The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney.
复制标题
进行性肾小球疾病对肾脏巨蛋白介导的内吞作用的影响。
DOI：
10.1093/ndt/gfq044
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Christensen,ErikI
中科院分区：
文献类型：
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作者：
Vinge,Lotte;Lees,GeorgeE;Nielsen,Rikke;Kashtan,CliffordE;Bahr,Anne;Christensen,ErikI
背景：一种X-连锁胶原病Alport综合征（XLAS）的狗模型被用来研究进行性肾小球疾病对巨蛋白介导的内吞作用的影响。在XLAS，肾小球基底膜的结构和功能的改变诱导进行性蛋白尿性nephropathy.Methods。进行调查，在男性XLAS犬和年龄匹配的正常男性同窝出生。用SDS-PAGE、免疫印迹和免疫组化方法对6只健康犬和6只XLAS犬在2、4、6、8和10月龄时的尿蛋白和巨蛋白介导的近曲小管内吞进行了检测。观察到显着的管状成分，这是由于巨蛋白对低分子量（LMW）配体的吸收发生逐渐变化。此外，存在于近端小管的管腔中的蛋白质过载超过了巨蛋白和辅助受体cubilin的重吸收能力，并导致组合的低分子量和高分子量（HMW）蛋白尿。此外，在XLAS狗的溶酶体的分布的变化表明在溶酶体降解模式的变化，在响应改变的内吞作用。结论。本研究表明，肾小球通透性增加，随后改变巨蛋白介导的和巨蛋白依赖cubilin介导的内吞作用导致部分低分子量蛋白尿和部分高分子量蛋白尿。
Background.A well-characterized dog model of the X-linked collagen disease Alport syndrome (XLAS) was used to study the effect of progressive glomerular disease on megalin-mediated endocytosis. In XLAS, altered structure and function of the glomerular basement membrane induces a progressive proteinuric nephropathy.Methods.The investigation was performed in male XLAS dogs and age-matched normal male littermates. The urine profile and megalin-mediated endocytosis in the proximal tubule of six healthy and six XLAS dogs were examined at 2, 4, 6, 8 and 10 months of age using SDS–PAGE, immunoblotting and immunohistochemistry.Results.Gradually increasing urinary excretion of proteins over time and a reduced content of the same proteins in proximal tubule cells were found. Besides the glomerular component of the proteinuria, a significant tubular component was seen, which is due to a progressive change in the uptake of low-molecular-weight (LMW) ligands by megalin. Furthermore, the protein overload present in the lumen of the proximal tubule exceeds the reabsorption capacity of megalin and the co-receptor cubilin and results in a combined low- and high-molecular-weight (HMW) proteinuria. Also, a shift in the distribution of lysosomes was seen in the XLAS dogs suggesting changes in the lysosomal degradation pattern in response to the altered endocytosis.Conclusions.The present study shows that the increased glomerular permeability and the subsequently altered megalin-mediated and megalin-dependent cubilin-mediated endocytosis lead to a partial LMW proteinuria and partial HMW proteinuria.