Dissection of Glomerular Transcriptional Profile in Patients With Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function
Dissection of Glomerular Transcriptional Profile in Patients With Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function
复制标题
糖尿病肾病患者肾小球转录谱的剖析：SRGAP2a 保护足细胞结构和功能。
DOI：
10.2337/db17-0755
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发表时间：
2018-04-01
期刊：
影响因子：
7.7
通讯作者：
Liu, Zhihong
中科院分区：
文献类型：
--
作者：
Pan, Yu;Jiang, Song;Liu, Zhihong
足细胞通过其叉指状足突在维持肾小球滤过功能中起关键作用。然而，足细胞骨架重排的机制仍不清楚。通过分析来自糖尿病肾病（DN）患者和对照供体的肾活检标本的转录谱，我们确定SLIT-ROBO rGTP酶激活蛋白2a（SRGAP 2a）是与2型DN中的蛋白尿和肾小球滤过强烈相关的主要枢纽基因之一。免疫荧光染色和Western印迹分析显示，人类和小鼠SRGAP 2a主要定位于足细胞，并在很大程度上与突触足蛋白共定位。此外，足细胞SRGAP 2a在DN患者和db/db小鼠中在mRNA和蛋白水平上下调。在用肿瘤生长因子-β或高浓度葡萄糖处理的培养足细胞中观察到SRGAP 2a减少。功能和机制研究表明，SRGAP 2a通过灭活RhoA/Cdc 42而不是Rac 1来抑制足细胞运动。SRGAP 2a在足细胞功能中的保护作用也在斑马鱼中得到证实，其中SRGAP 2a（斑马鱼中的SRGAP 2直系同源物）的敲低重现足细胞足突消失。最后，通过施用表达SRGAP 2a的腺病毒来增加db/db小鼠中的足细胞SRGAP 2a水平显著减轻足细胞损伤和蛋白尿。结果表明，SRGAP 2a通过抑制足细胞迁移来保护足细胞。
Podocytes play a pivotal role in maintaining glomerular filtration function through their interdigitated foot processes. However, the mechanisms that govern the podocyte cytoskeletal rearrangement remain unclear. Through analyzing the transcriptional profile of renal biopsy specimens from patients with diabetic nephropathy (DN) and control donors, we identify SLIT-ROBO rGTPase-activating protein 2a (SRGAP2a) as one of the main hub genes strongly associated with proteinuria and glomerular filtration in type 2 DN. Immunofluorescence staining and Western blot analysis revealed that human and mouse SRGAP2a is primarily localized at podocytes and largely colocalized with synaptopodin. Moreover, podocyte SRGAP2a is downregulated in patients with DN and db/db mice at both the mRNA and the protein level. SRGAP2a reduction is observed in cultured podocytes treated with tumor growth factor-beta or high concentrations of glucose. Functional and mechanistic studies show that SRGAP2a suppresses podocytemotility through inactivating RhoA/Cdc42 but not Rac1. The protective role of SRGAP2a in podocyte function also is confirmed in zebrafish, in which knockdown of SRGAP2a, a SRGAP2 ortholog in zebrafish, recapitulates podocyte foot process effacement. Finally, increasing podocyte SRGAP2a levels in db/db mice through administration of adenovirus-expressing SRGAP2a significantly mitigates podocyte injury and proteinuria. The results demonstrate that SRGAP2a protects podocytes by suppressing podocyte migration.