Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm-Horsfall protein.
Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm-Horsfall protein.
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DOI：
10.1007/s00240-010-0353-7
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发表时间：
2011-08
影响因子：
--
通讯作者：
Wesson, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Viswanathan, Pragasam;Rimer, Jeffrey D.;Kolbach, Ann M.;Ward, Michael D.;Kleinman, Jack G.;Wesson, Jeffrey A.
Tamm-Horsfall蛋白（THP）被认为通过抑制一水草酸钙（COM）聚集来防止COM结石形成。几项研究报道，结石形成者产生的THP具有降低的糖基化水平，特别是唾液酸水平，这导致负电荷减少。在这项研究中，正常的THP神经氨酸酶处理，以消除唾液酸残基，证实了等电点转移到更高的pH值。COM聚集试验表明，去唾液酸化的THP（双THP）促进COM聚集，而正常的THP抑制聚集。在150 mM NaCl中，在ds-THP浓度≥1 µg/mL的溶液中出现的蛋白质聚集体与COM聚集促进相关，这意味着ds-THP聚集诱导COM聚集。的ds-THP的聚集促进作用是独立的pH值高于其等电点，但在低离子强度，其中蛋白质聚集大大减少，大大降低。COM聚集促进在ds-THP与COM的质量比为约0.025时最大化，这可以通过以下模型来解释，其中ds-THP聚集体的部分COM表面覆盖通过桥接相对的COM表面来促进晶体聚集，而更高的表面覆盖导致吸附的ds-THP聚集体之间的排斥。因此，THP的去唾液酸化通过诱导蛋白质聚集和随后的COM聚集（一种有利于肾结石形成的条件）明显地废除了THP的正常防御作用。
Tamm-Horsfall protein (THP) is thought to protect against calcium oxalate monohydrate (COM) stone formation by inhibiting COM aggregation. Several studies reported that stone formers produce THP with reduced levels of glycosylation, particularly sialic acid levels, which leads to reduced negative charge. In this study, normal THP was treated with neuraminidase to remove sialic acid residues, confirmed by an isoelectric point shift to higher pH. COM aggregation assays revealed that desialylated THP (ds-THP) promoted COM aggregation, while normal THP inhibited aggregation. The appearance of protein aggregates in solutions at ds-THP concentrations ≥1 µg/mL in 150 mM NaCl correlated with COM aggregation promotion, implying that ds-THP aggregation induced COM aggregation. The aggregation-promoting effect of the ds-THP was independent of pH above its isoelectric point, but was substantially reduced at low ionic strength, where protein aggregation was much reduced. COM aggregation promotion was maximized at a ds-THP to COM mass ratio of ~0.025, which can be explained by a model wherein partial COM surface coverage by ds-THP aggregates promotes crystal aggregation by bridging opposing COM surfaces, whereas higher surface coverage leads to repulsion between adsorbed ds-THP aggregates. Thus, desialylation of THP apparently abrogates a normal defensive action of THP by inducing protein aggregation, and subsequently COM aggregation, a condition that favors kidney stone formation.
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