Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2
Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2
复制标题
MAGI2-RapGEF2-Rap1 信号传导的破坏导致 MAGI2 突变引起的先天性肾病综合征的足细胞功能障碍
DOI：
10.1016/j.kint.2019.03.016
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发表时间：
2019
影响因子：
19.6
通讯作者：
Kaufman Lewis
中科院分区：
文献类型：
--
作者：
Zhu Bingbing;Cao Aili;Li Jianhua;Young James;Wong Jenny;Ashraf Shazia;Bierzynska Agnieszka;Menon Madhav C;Hou Steven;Sawyers Charles;Campbell Kirk N;Saleem Moin A;He John C;Hildebr;t Friedhelm;DAgati Vivette D;Peng Wen;Kaufman Lewis
膜相关鸟苷酸激酶2 （MAGI2）在足细胞中的重要作用，由MAGI2基因突变引起的重度肾小球硬化小鼠和先天性肾病综合征（CNS）患者的表型表明。在这里，我们发现MAGI2与Rap1鸟嘌呤核苷酸交换因子RapGEF2形成复合物，并且当表达MAGI2 CNS变体时，该复合物丢失。RapGEF2与野生型MAGI2（而不是MAGI2 CNS变体）共表达，增强了小GTPase Rap1的激活，Rap1是足细胞的中心信号节点。在小鼠中，足细胞特异性RapGEF2缺失导致自发性肾小球硬化，其定性肾小球特征与MAGI2敲除小鼠相当。在人足细胞中敲低RapGEF2或MAGI2会导致Rap1激活水平和Rap1介导的下游信号水平的类似降低。此外，表达MAGI2中枢神经系统变异的人足细胞表现出严重的细胞形态异常和肌动蛋白细胞骨架组织的急剧丧失，这些特征通过非MAGI2依赖的上游途径被Rap1的药理激活完全挽救。最后，对先天性肾病综合征和MAGI2突变患者肾切片的免疫染色显示足细胞rap1介导的信号传导减少。因此，MAGI2-RapGEF2-Rap1信号对于正常足细胞功能至关重要。因此，这一途径的破坏是由MAGI2 CNS突变引起肾脏表型的重要原因。
The essential role of membrane associated guanylate kinase 2 (MAGI2) in podocytes is indicated by the phenotypes of severe glomerulosclerosis of both MAGI2 knockout mice and in patients with congenital nephrotic syndrome (CNS) caused by mutations in MAGI2. Here, we show that MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor, RapGEF2, and that this complex is lost when expressing MAGI2 CNS variants. Co-expression of RapGEF2 with wild-type MAGI2, but not MAGI2 CNS variants, enhanced activation of the small GTPase Rap1, a central signaling node in podocytes. In mice, podocyte-specific RapGEF2 deletion resulted in spontaneous glomerulosclerosis, with qualitative glomerular features comparable to MAGI2 knockout mice. Knockdown of RapGEF2 or MAGI2 in human podocytes caused similar reductions in levels of Rap1 activation and Rap1-mediated downstream signaling. Furthermore, human podocytes expressing MAGI2 CNS variants show severe abnormalities of cellular morphology and dramatic loss of actin cytoskeletal organization, features completely rescued by pharmacological activation of Rap1 via a non-MAGI2 dependent upstream pathway. Finally, immunostaining of kidney sections from patients with congenital nephrotic syndrome and MAGI2 mutations showed reduced podocyte Rap1-mediated signaling. Thus, MAGI2-RapGEF2-Rap1 signaling is essential for normal podocyte function. Hence, disruption of this pathway is an important cause of the renal phenotype induced by MAGI2 CNS mutations.