Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats
Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats
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DOI：
10.1152/ajprenal.00329.2012
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发表时间：
2013-03-01
影响因子：
4.2
通讯作者：
Isaka, Yoshitaka
中科院分区：
文献类型：
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作者：
Matsui, Isao;Hamano, Takayuki;Isaka, Yoshitaka
Matsui I，Hamano T，Mikami S，Inoue K，Shimomura A，Nagasawa Y，Yogami T，Ohnishi T，Fujii N，中野C，Kusunoki Y，Kitamura H，Iwatani H，Takabatake Y，Kaimori JY，Matsuba G，Okoshi K，Kimura-Suda H，Tsubakihara Y，Rakugi H，Isaka Y.胎球蛋白-A在肾小管内滞留对大鼠肾钙质沉着的保护作用美国肾脏生理学杂志304：F751-F760，2013年。首次发表于2013年1月23日; doi：10.1152/ajprenal.00329.2012。血清糖蛋白胎球蛋白-A是骨外钙化的重要抑制剂。胎球蛋白-A的重要性已在胎球蛋白-A缺失小鼠中得到证实，这些小鼠发生广泛的骨外钙化，包括肾脏。然而，胎球蛋白A如何保护肾脏免受肾钙质沉着的机制仍不确定。在这里，我们证明了肾小管内胎球蛋白-A在预防近端小管肾钙质沉着症中发挥作用。虽然正常大鼠肾脏不表达胎球蛋白-A的mRNA，我们发现点状免疫组化染色的胎球蛋白-A主要在S1段的近端小管。染色模式表明，胎球蛋白-A通过狭缝隔膜，在近端小管腔中行进，并通过巨蛋白介导的内吞作用被引入近端小管细胞。为了验证这一假设，我们通过静脉注射组氨酸标记的可溶性受体相关蛋白（His-SRAP），一种巨蛋白抑制剂，抑制了巨蛋白的功能。His-SRAP注射减少了近端小管中的胎球蛋白-A染色，并导致胎球蛋白-A的尿排泄。我们进一步分析了胎球蛋白-A在肾钙质沉着症中的作用。连续注射甲状旁腺激素（PTH）1-34可引起大鼠肾近曲小管钙沉着。His-sRAP保留胎球蛋白-A在肾小管腔，从而保护PTH处理的大鼠的肾脏免于钙化。我们的研究结果表明，肾小管腔胎球蛋白-A工程作为一种天然的抑制剂，对钙化的近端小管下PTH负载的条件。
Matsui I, Hamano T, Mikami S, Inoue K, Shimomura A, Nagasawa Y, Michigami T, Ohnishi T, Fujii N, Nakano C, Kusunoki Y, Kitamura H, Iwatani H, Takabatake Y, Kaimori JY, Matsuba G, Okoshi K, Kimura-Suda H, Tsubakihara Y, Rakugi H, Isaka Y. Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats. Am J Physiol Renal Physiol 304:F751-F760, 2013. First published January 23, 2013; doi:10.1152/ajprenal.00329.2012. The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1-34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin-A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition.