Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases.
Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases.
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DOI：
10.1016/j.kint.2017.12.028
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发表时间：
2018-06
影响因子：
19.6
通讯作者：
Schiffer M
中科院分区：
文献类型：
--
作者：
Sever S;Schiffer M
蛋白尿涵盖多种病因，包括遗传性疾病和获得性形式，例如糖尿病和高血压肾病。蛋白尿的基础是肾小球滤过屏障的大小选择性紊乱，这在很大程度上取决于足细胞：覆盖肾小球外表面的终末分化上皮细胞类型。足细胞结构受损是肾小球损伤的最早迹象之一。不同动物模型和足细胞细胞培养的表型牢固地确立了肌动蛋白细胞骨架在维持功能性足细胞结构中的重要作用。足细胞足突 (FP) 是基于肌动蛋白的膜延伸，包含两个特殊且分子上不同的控制肌动蛋白动力学的“中枢”：狭缝隔膜和粘着斑。虽然 FP 的损失包括裂隙隔膜多蛋白复合物的分解，但只要细胞附着在肾小球基底膜上，粘着斑就会成为滤过流引起的压力被 FP 中肌动蛋白网络产生的力抵消的部位。过去二十年的大量研究发现肌动蛋白结合蛋白和调节蛋白以及整合素是足细胞粘着斑信号传导和肌动蛋白动力学的重要组成部分，这表明其中一些可能成为蛋白尿性肾病的新型药物靶标。在这里，我们回顾了支持这一观点的证据，即当前慢性肾脏病 (CKD) 的治疗有益且直接靶向与粘着斑相关的足细胞肌动蛋白细胞骨架，并表明针对 FP 中粘着斑调节的肌动蛋白细胞骨架的治疗试剂有可能使 CKD 治疗现代化
Proteinuria encompasses diverse etiologies including both genetic diseases and acquired forms such as diabetic and hypertensive nephropathy. The basis of proteinuria is a disturbance in size selectivity of the glomerular filtration barrier, which largely depends on the podocyte: a terminally differentiated epithelial cell type covering the outer surface of the glomerulus. Compromised podocyte structure is one of the earliest signs of glomerular injury. The phenotype of diverse animal models and podocyte cell culture firmly established the essential role of the actin cytoskeleton in maintaining functional podocyte structure. Podocyte foot processes (FPs), actin-based membrane extensions, contain two specially and molecularly distinct “hubs” that control actin dynamics: a slit diaphragm and focal adhesions. While loss of FPs, encompasses dis-assembly of slit diaphragm multiprotein complexes, as long as cells are attached to the glomerular basement membrane, focal adhesions will be the sites in which stress due to filtration flow is counteracted by forces generated by the actin network in FPs. Numerous studies within last twenty years identified actin binding and regulatory proteins as well as integrins as essential components of signaling and actin dynamics at focal adhesions in podocytes, suggesting that some of them might become novel druggable targets for proteinuric kidney diseases. Here we review evidence supporting the idea that current treatments for chronic kidney diseases (CKD) beneficially and directly target the podocyte actin cytoskeleton associated with focal adhesions and suggest that therapeutic reagents that target the focal adhesion-regulated actin cytoskeleton in FPs have potential to modernize treatments for CKD
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通过块面扫描电子显微镜揭示的足细胞的三维结构。
影响因子：
4.6
作者：
Ichimura K;Miyazaki N;Sadayama S;Murata K;Koike M;Nakamura K;Ohta K;Sakai T
通讯作者：
Sakai T
影响因子：
82.9
作者：
Hayek SS;Koh KH;Grams ME;Wei C;Ko YA;Li J;Samelko B;Lee H;Dande RR;Lee HW;Hahm E;Peev V;Tracy M;Tardi NJ;Gupta V;Altintas MM;Garborcauskas G;Stojanovic N;Winkler CA;Lipkowitz MS;Tin A;Inker LA;Levey AS;Zeier M;Freedman BI;Kopp JB;Skorecki K;Coresh J;Quyyumi AA;Sever S;Reiser J
通讯作者：
Reiser J
影响因子：
6.8
作者：
Bergon, Enrique;Granados, Rosario;Bergon, Marta
通讯作者：
Bergon, Marta
影响因子：
19.6
作者：
Durvasula, RV;Petermann, AT;Shankland, SJ
通讯作者：
Shankland, SJ
影响因子：
15.9
作者：
Gloy, J;Henger, A;Pavenstadt, H
通讯作者：
Pavenstadt, H