Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models
Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models
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DOI：
10.1038/nm.3843
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发表时间：
2015-06-01
期刊：
影响因子：
82.9
通讯作者：
Sever, Sanja
中科院分区：
文献类型：
--
作者：
Schiffer, Mario;Teng, Beina;Sever, Sanja
足细胞肌动蛋白细胞骨架的失调是一种常见的慢性肾脏疾病(CKD)蛋白尿的发病机制。GTPase Dynamin通过与肌动蛋白的直接相互作用参与足细胞结构的维持。此外，动力蛋白倾向于以肌动蛋白依赖的方式齐聚成高阶结构，并将肌动蛋白微丝交联成高阶结构，这与肌动蛋白聚合的增加和细胞内肌动蛋白细胞骨架的整体组织有关。我们发现，使用小分子Bis-T-23，促进肌动蛋白依赖的动力蛋白寡聚，从而增加受损足细胞中的肌动蛋白聚合，足以改善短暂性肾脏疾病和CKD的不同模型的肾脏健康。特别是，在这些肾脏疾病模型中应用Bis-T-23恢复了足细胞足突的正常超微结构，降低了蛋白尿，减少了系膜基质中IV型胶原的沉积，减少了系膜基质的扩张，延长了寿命。这些结果进一步证实肾脏足细胞肌动蛋白细胞骨架的改变是CKD的共同标志，同时也强调了受损肾小球的巨大再生潜力，并确认Dynamin的寡聚循环是治疗CKD的一个有吸引力的潜在治疗靶点。
Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.