Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation
Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation
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DOI：
10.1111/j.1523-1755.2004.00867.x
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发表时间：
2004-09-01
影响因子：
19.6
通讯作者：
Wu, XR
中科院分区：
文献类型：
--
作者：
Mo, L;Huang, HY;Wu, XR
背景哺乳动物肾脏的小管液通常被矿物盐过饱和，但在正常条件下很少发生结晶。肾脏避免有害晶体形成的独特能力长期以来一直归因于尿大分子的抑制活性，尽管很少进行体内研究来检验这一假设。在这里，我们研究的作用Tamm-Horsfall蛋白（THP），主要的尿蛋白，在尿防御肾钙晶体形成，使用THP敲除模型，我们最近开发的。使用von Kossa染色检查野生型和THP敲除小鼠肾钙晶体的自发形成。这些小鼠对实验诱导的肾晶体形成的易感性通过给予小鼠乙二醇（草酸盐的前体）和维生素D-3（其增加钙吸收）来评估。肾组织钙结晶的显示采用vonKossa染色、偏振光暗视野显微镜和扫描电镜。小鼠胚胎干细胞中THP基因的失活导致成年肾脏中钙晶体的自发形成。过量摄入钙和草酸盐，最常见类型的人类肾结石的前体，显着增加的频率和严重性的肾钙晶体形成THP缺乏，但不是在野生型小鼠。在高钙/草酸盐条件下，THP的缺乏在肾上皮细胞中触发骨桥蛋白（OPN）的显著适应性诱导，骨桥蛋白是骨矿化和血管钙化的有效抑制剂。因此，OPN可能是一种诱导型钙结晶抑制剂，而THP可能是一种组成型的钙结晶抑制剂，其作用更明显。这些结果提供了第一个体内证据，证明THP是一种关键的泌尿防御因子，并表明其缺乏可能是人类肾结石的重要促成因素，这种疾病每年困扰着世界上数千万人。
Background. The tubular fluid of the mammalian kidney is often supersaturated with mineral salts, but crystallization rarely occurs under normal conditions. The unique ability of the kidney to avoid harmful crystal formation has long been attributed to the inhibitory activity of the urinary macromolecules, although few in vivo studies have been carried out to examine this hypothesis. Here we examined the role of Tamm-Horsfall protein (THP), the principal urinary protein, in urinary defense against renal calcium crystal formation, using a THP knockout model that we recently developed.Methods. Wild-type and THP knockout mice were examined for the spontaneous formation of renal calcium crystals using von Kossa staining. The susceptibility of these mice to experimentally induced renal crystal formation was evaluated by administering mice with ethylene glycol, a precursor of oxalate, and vitamin D-3, which increases calcium absorption. Renal calcium crystals were visualized by von Kossa stain, dark field microscopy with polarized light and scanning electron microscopy.Results. Inactivating the THP gene in mouse embryonic stem cells results in spontaneous formation of calcium crystals in adult kidneys. Excessive intake of calcium and oxalate, precursors of the most common type of human renal stones, dramatically increases both the frequency and the severity of renal calcium crystal formation in THP-deficient, but not in wild-type mice. Under high calcium/oxalate conditions, the absence of THP triggers a marked, adaptive induction in renal epithelial cells of osteopontin (OPN), a potent inhibitor of bone mineralization and vascular calcification. Thus, OPN may serve as an inducible inhibitor of calcium crystallization, whereas THP can serve as a constitutive and apparently more effective inhibitor.Conclusion. These results provide the first in vivo evidence that THP is a critical urinary defense factor and suggest that its deficiency could be an important contributing factor in human nephrolithiasis, a condition afflicting tens of millions of people in the world annually.