The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease.
The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease.
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DOI：
10.1016/j.kint.2020.05.040
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发表时间：
2020-10
影响因子：
19.6
通讯作者：
Gallop JL
中科院分区：
文献类型：
--
作者：
Berquez M;Gadsby JR;Festa BP;Butler R;Jackson SP;Berno V;Luciani A;Devuyst O;Gallop JL
编码磷脂酰肌醇 [PI] 4,5-二磷酸 [PI(4,5)P2] 5-磷酸酶 OCRL 的 OCRL 基因中的功能缺失突变会导致 Lowe 综合征和 Dent 病 2 中的内吞作用缺陷和近端小管功能障碍。该缺陷是由于 PI(4,5)P2 水平升高和异常肌动蛋白聚合导致的，从而阻碍了内体运输。 PI 3-磷酸[PI(3)P] 最近被确定为肌动蛋白途径中PI(4,5)P2 的共激活剂。在这里，我们测试了这样的假设：磷酸肌醇 3-激酶 (PI3K) 抑制剂可以通过重新平衡肌动蛋白机制的磷酸肌醇信号来挽救 OCRL 损失造成的内吞缺陷。广泛的 PI3K 抑制剂 copanlisib 和 IA 类 p110α PI3K 抑制剂 alpelisib 可在体外减少 OCRL 缺陷的人肾细胞中的异常肌动蛋白聚合。 alpelisib 治疗后，PI 3,4,5-三磷酸、PI(4,5)P2 和 PI(3)P 水平均降低，并且 PI3K 催化亚基 p110α 的 siRNA 敲低复制了肌动蛋白表型。在人源化 OcrlY/- 小鼠模型中，alpelisib 减少了内体肌动蛋白染色，同时恢复了近端小管细胞质膜上的应力纤维结构和巨蛋白水平，这反映在体内低分子量蛋白质的内吞摄取的改善。因此，我们的研究结果支持近曲小管中磷酸肌醇脂质、肌动蛋白聚合和内吞运输之间的联系，并为在 Lowe 综合征/Dent 病 2 中重新利用 alpelisib 提供了概念验证。
Loss-of-function mutations in the OCRL gene, which encodes the phosphatidylinositol [PI] 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase OCRL, cause defective endocytosis and proximal tubule dysfunction in Lowe syndrome and Dent disease 2. The defect is due to increased levels of PI(4,5)P2 and aberrant actin polymerization, blocking endosomal trafficking. PI 3-phosphate [PI(3)P] has been recently identified as a coactivator with PI(4,5)P2 in the actin pathway. Here, we tested the hypothesis that phosphoinositide 3-kinase (PI3K) inhibitors may rescue the endocytic defect imparted by OCRL loss, by rebalancing phosphoinositide signals to the actin machinery. The broad-range PI3K inhibitor copanlisib and class IA p110α PI3K inhibitor alpelisib reduced aberrant actin polymerization in OCRL-deficient human kidney cells in vitro. Levels of PI 3,4,5-trisphosphate, PI(4,5)P2 and PI(3)P were all reduced with alpelisib treatment, and siRNA knockdown of the PI3K catalytic subunit p110α phenocopied the actin phenotype. In a humanized OcrlY/- mouse model, alpelisib reduced endosomal actin staining while restoring stress fiber architecture and levels of megalin at the plasma membrane of proximal tubule cells, reflected by improved endocytic uptake of low molecular weight proteins in vivo. Thus, our findings support the link between phosphoinositide lipids, actin polymerization and endocytic trafficking in the proximal tubule and represent a proof-of-concept for repurposing alpelisib in Lowe syndrome/Dent disease 2.
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DOI：
10.1042/bj20090428
发表时间：
2009-07-29
期刊：
The Biochemical journal
影响因子：
--
作者：
Hammond GR;Schiavo G;Irvine RF
通讯作者：
Irvine RF
影响因子：
13.6
作者：
Bothwell, Susan P.;Chan, Emily;Nussbaum, Robert L.
通讯作者：
Nussbaum, Robert L.
DOI：
10.1073/pnas.1305286110
发表时间：
2013-04-30
影响因子：
11.1
作者：
Gallop，Jennifer L.;Walrant，Astrid;Kirschner，Marc W.
通讯作者：
Kirschner，Marc W.
影响因子：
168.9
作者：
Devuyst, Olivier;Knoers, Nine V. A. M.;Remuzzi, Giuseppe;Schaefer, Franz
通讯作者：
Schaefer, Franz
影响因子：
3.5
作者：
Montjean, Rodrick;Aoidi, Rifdat;Dorseuil, Olivier
通讯作者：
Dorseuil, Olivier