The glomerular filtration barrier: a structural target for novel kidney therapies.
The glomerular filtration barrier: a structural target for novel kidney therapies.
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DOI：
10.1038/s41573-021-00242-0
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Duffield JS
中科院分区：
文献类型：
--
作者：
Daehn IS;Duffield JS
正常肾功能丧失影响超过10%的人口，并导致发病率和死亡率。肾脏疾病目前用免疫抑制剂、抗高血压药和利尿剂治疗，但效果有限。大多数肾脏疾病的特征是肾小球滤过屏障（GFB）的破坏。特化的足细胞维持足动脉b，结构-功能实验和足细胞与其他足动脉b细胞之间细胞间通讯的研究，结合遗传学和基因组学的进展，为直接干预足动脉b的新一代疗法奠定了基础。这些抑制剂包括载脂蛋白L1 （APOL1）、短瞬时受体电位通道（TRPCs）、可溶性fms样酪氨酸激酶1 （sFLT1；也称为可溶性血管内皮生长因子受体1）、迂回同源物2 （ROBO2）、内皮素受体A、可溶性尿激酶纤溶酶原激活物表面受体（suPAR）和辅酶Q10 （CoQ10）底物中间体。这些分子靶点集中在GFB生物学的两个关键组成部分：线粒体功能和肌动蛋白-肌球蛋白收缩机制。本综述讨论了维持GFB完整性的治疗方法和发展，以及这一不断发展的领域中出现的问题。许多肾脏疾病的特征是形成血液和尿液界面的肾小球滤过屏障的破坏。在这篇综述中，dahn和Duffield讨论了针对这一屏障成分的策略，重点是控制线粒体功能和肌动蛋白-肌球蛋白机制的机制，以改善肾脏疾病患者的肾功能。
Loss of normal kidney function affects more than 10% of the population and contributes to morbidity and mortality. Kidney diseases are currently treated with immunosuppressive agents, antihypertensives and diuretics with partial but limited success. Most kidney disease is characterized by breakdown of the glomerular filtration barrier (GFB). Specialized podocyte cells maintain the GFB, and structure–function experiments and studies of intercellular communication between the podocytes and other GFB cells, combined with advances from genetics and genomics, have laid the groundwork for a new generation of therapies that directly intervene at the GFB. These include inhibitors of apolipoprotein L1 (APOL1), short transient receptor potential channels (TRPCs), soluble fms-like tyrosine kinase 1 (sFLT1; also known as soluble vascular endothelial growth factor receptor 1), roundabout homologue 2 (ROBO2), endothelin receptor A, soluble urokinase plasminogen activator surface receptor (suPAR) and substrate intermediates for coenzyme Q10 (CoQ10). These molecular targets converge on two key components of GFB biology: mitochondrial function and the actin–myosin contractile machinery. This Review discusses therapies and developments focused on maintaining GFB integrity, and the emerging questions in this evolving field. Numerous kidney diseases are characterized by a breakdown of the glomerular filtration barrier, which forms the interface between the blood and urine. In this Review, Daehn and Duffield discuss strategies to target components of this barrier, focusing on mechanisms to control mitochondrial function and the actin–myosin machinery, to improve kidney function in individuals with kidney diseases.
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