Urinary secretion and extracellular aggregation of mutant uromodulin isoforms
Urinary secretion and extracellular aggregation of mutant uromodulin isoforms
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DOI：
10.1038/ki.2011.456
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发表时间：
2012-04-01
影响因子：
19.6
通讯作者：
Rampoldi, Luca
中科院分区：
文献类型：
--
作者：
Schaeffer, Celine;Cattaneo, Angela;Rampoldi, Luca
尿调蛋白仅在粗升肢中表达，是尿液中最丰富的蛋白质，存在于高分子量聚合物中。其生物学功能尚不清楚，但被认为对尿路感染、草酸钙晶体形成和厚升肢水盐平衡的调节有保护作用。尿调蛋白突变是常染色体显性肾病的原因，其特征是尿浓缩能力缺陷、高尿酸血症、痛风、小管间质纤维化、肾囊肿和慢性肾病。先前的体外研究发现，保留在内质网是所有尿调蛋白突变亚型的共同特征。在体外和体内实验中，我们都发现突变异构体部分地逃脱了内质网的滞留，到达质膜，在那里它们形成了大的细胞外聚集体，对共表达的野生型蛋白具有显性的负面影响。值得注意的是，在携带尿调蛋白突变的患者中检测到突变的尿调蛋白排泄。因此，我们的研究结果表明，突变型尿调蛋白可以通过细胞内和细胞外形式发挥功能获得效应。肾脏国际（2012）81,769-778；doi: 10.1038 / ki.2011.456;2012年1月11日在线发布
Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra-and extracellular forms of the protein. Kidney International (2012) 81, 769-778; doi:10.1038/ki.2011.456; published online 11 January 2012