PAI-1 is a critical regulator of FGF23 homeostasis.
PAI-1 is a critical regulator of FGF23 homeostasis.
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DOI：
10.1126/sciadv.1603259
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发表时间：
2017-09
期刊：
影响因子：
13.6
通讯作者：
Vaughan DE
中科院分区：
文献类型：
--
作者：
Eren M;Place AT;Thomas PM;Flevaris P;Miyata T;Vaughan DE
PAI-1的药理抑制增强了FGF23的蛋白降解清除。成纤维细胞生长因子23(FGF23)是一种骨源性磷酸激素，其水平升高与许多病理疾病有关，包括慢性肾脏疾病、心肌肥厚和充血性心力衰竭。目前，尚无特效治疗方法可用于降低血浆FGF23水平。我们最近报道，遗传性纤溶酶原激活物抑制物-1(PAI-1)缺乏可以显著降低循环中FGF23的水平，同时延长Klotho缺陷小鼠的寿命。我们进一步研究了PAI-1对FGF23动态平衡的影响。与野生型相比，PAI-1转基因过表达导致FGF23水平增加三倍。此外，小分子PAI-1拮抗剂TM5441对PAI-1活性的药理调节显著降低了PAI-1转基因和Klotho缺陷小鼠的FGF23水平。此外，TM5441治疗或PAI-1缺乏显著加快了内源性FGF23和重组人FGF23从急性肾损伤小鼠循环中的清除。在此基础上，我们研究了纤溶酶原激活剂、组织型纤溶酶原激活剂(TPA)和尿激酶型纤溶酶原激活剂(UPA)对FGF23的影响。我们证明了这两个PA都直接切割FGF23；然而，尚不清楚PA产生的FGF23肽是否保留或获得影响完整FGF23的结合和/或信号特性的功能。PAI-1抑制依赖PA的FGF23的切割，TM5441抑制PAI-1使FGF23的蛋白降解恢复。此外，自上而下的蛋白质组学分析表明，tPA在多个精氨酸上切割FGF23，包括前转换酶敏感部位R176。综上所述，我们的结果表明，PAI-1阻止PA驱动的FGF23的蛋白降解，抑制PAI-1为预防FGF23增加的病理后果提供了一种新的治疗途径。
Pharmacological inhibition of PAI-1 augments proteolytic clearance of FGF23. Elevated levels of fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone, are associated with a number of pathologic conditions including chronic kidney disease, cardiac hypertrophy, and congestive heart failure. Currently, there are no specific treatments available to lower plasma FGF23 levels. We have recently reported that genetic plasminogen activator inhibitor–1 (PAI-1) deficiency provided a significant reduction in circulating FGF23 levels while simultaneously prolonging the life span of Klotho-deficient mice. We extend our investigations into the effect of PAI-1 on FGF23 homeostasis. Transgenic overexpression of PAI-1 resulted in threefold increase in FGF23 levels compared to wild-type littermates. Moreover, pharmacological modulation of PAI-1 activity with the small-molecule PAI-1 antagonist TM5441 significantly reduced FGF23 levels in PAI-1 transgenic and Klotho-deficient mice. In addition, TM5441 treatment or PAI-1 deficiency significantly accelerated the clearance of endogenous FGF23 and recombinant human FGF23 from circulation in mice with acute kidney injury. On the basis of these observations, we studied the effects of plasminogen activators (PAs), tissue-type PA (tPA) and urokinase-type PA (uPA), on FGF23. We demonstrate that both PAs directly cleave FGF23; however, it is not known whether the PA-generated FGF23 peptides retain or acquire functions that affect binding and/or signaling properties of intact FGF23. PAI-1 inhibits the PA-dependent cleavage of FGF23, and TM5441 inhibition of PAI-1 restores the proteolysis of FGF23. Furthermore, top-down proteomic analysis indicates that tPA cleaves FGF23 at multiple arginines including the proconvertase sensitive site R176. In summary, our results indicate that PAI-1 prevents the PA-driven proteolysis of FGF23 and PAI-1 inhibition provides a novel therapeutic approach to prevent the pathologic consequences of increased FGF23.
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DOI：
10.1038/nrm3528
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
5.3
作者：
Goetz, Regina;Beenken, Andrew;Mohammadi, Moosa
通讯作者：
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影响因子：
8.2
作者：
Haussler, Mark R.;Whitfield, G. Kerr;Kaneko, Ichiro;Forster, Ryan;Saini, Rimpi;Hsieh, Jui-Cheng;Haussler, Carol A.;Jurutka, Peter W.
通讯作者：
Jurutka, Peter W.
影响因子：
4.8
作者：
Coombs, GS;Bergstrom, RC;Corey, DR
通讯作者：
Corey, DR
DOI：
10.1073/pnas.1120437109
发表时间：
2012-07-24
影响因子：
11.1
作者：
Elzi, David J.;Lai, Yanlai;Shiio, Yuzuru
通讯作者：
Shiio, Yuzuru