Renal ADAM10 and 17: Their Physiological and Medical Meanings.
Renal ADAM10 and 17: Their Physiological and Medical Meanings.
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DOI：
10.3389/fcell.2018.00153
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发表时间：
2018
影响因子：
5.5
通讯作者：
Ito A
中科院分区：
文献类型：
--
作者：
Kato T;Hagiyama M;Ito A
解整合素和金属蛋白酶 (ADAM) 是 Zn2+ 依赖性跨膜和分泌型金属蛋白酶超家族，即所谓的“分子剪刀”，它们由 N 端信号序列、前结构域、锌结合金属蛋白酶结构域、解整合素结构域、富含半胱氨酸的结构域、跨膜结构域和胞质尾部组成。 ADAM 将不同跨膜分子的胞外域蛋白水解加工成生物活性介质。这篇综述总结了他们最著名的成员 ADAM10 和 17，重点关注肾脏。 ADAM10在肾小管细胞中表达，影响特定刷状缘基因的表达，其激活与一些肾脏疾病有关。 ADAM17在正常肾脏中表达较弱，但在肾小管、毛细血管、肾小球和系膜中显着诱导表达，并参与间质纤维化和肾小管萎缩。到目前为止，已在肾脏中鉴定出各种底物。脱落的片段成为释放的配体，例如Notch和EGFR配体，并充当包括CXCL16在内的趋化因子。它们的胞外域脱落与炎症、间质纤维化和肾损伤等病理因素密切相关。此外，两种 ADAM 的底物都含有在质膜上发挥重要作用的分子，例如 meaprin、E-cadherin、Klotho 和 CADM1。通过释放到尿液中，脱落的产物可用于肾脏疾病的生物标志物，但 ADAM10 和 17 本身也是值得注意的生物标志物。此外，基于小分子、抗体及其重组前结构域等各种策略的 ADAM10 和/或 17 抑制是有价值的，因为它们可能保护肾组织并促进肾再生。尽管抑制剂的时间和空间调控是有待解决的问题，但它们的抑制剂可能对肾脏疾病有用。
A disintegrin and metalloproteinases (ADAMs) are a Zn2+-dependent transmembrane and secreted metalloprotease superfamily, so-called “molecular scissors,” and they consist of an N-terminal signal sequence, a prodomain, zinc-binding metalloprotease domain, disintegrin domain, cysteine-rich domain, transmembrane domain and cytoplasmic tail. ADAMs perform proteolytic processing of the ectodomains of diverse transmembrane molecules into bioactive mediators. This review summarizes on their most well-known members, ADAM10 and 17, focusing on the kidneys. ADAM10 is expressed in renal tubular cells and affects the expression of specific brush border genes, and its activation is involved in some renal diseases. ADAM17 is weakly expressed in normal kidneys, but its expression is markedly induced in the tubules, capillaries, glomeruli, and mesangium, and it is involved in interstitial fibrosis and tubular atrophy. So far, the various substrates have been identified in the kidneys. Shedding fragments become released ligands, such as Notch and EGFR ligands, and act as the chemoattractant factors including CXCL16. Their ectodomain shedding is closely correlated with pathological factors, which include inflammation, interstitial fibrosis, and renal injury. Also, the substrates of both ADAMs contain the molecules that play important roles at the plasma membrane, such as meaprin, E-cadherin, Klotho, and CADM1. By being released into urine, the shedding products could be useful for biomarkers of renal diseases, but ADAM10 and 17 per se are also notable as biomarkers. Furthermore, ADAM10 and/or 17 inhibitions based on various strategies such as small molecules, antibodies, and their recombinant prodomains are valuable, because they potentially protect renal tissues and promote renal regeneration. Although temporal and spatial regulations of inhibitors are problems to be solved, their inhibitors could be useful for renal diseases.