Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant α-actinin-4
Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant α-actinin-4
复制标题
DOI：
10.1097/01.asn.0000059864.88610.5e
复制
发表时间：
2003-05-01
影响因子：
13.6
通讯作者：
Kennedy, CRJ
中科院分区：
文献类型：
--
作者：
Michaud, JL;Lemieux, LI;Kennedy, CRJ
编码 α-肌动蛋白-4 (ACTN4)（一种肌动蛋白交联蛋白）的基因突变与常染色体显性局灶节段性肾小球硬化症 (FSGS) 相关。为了更好地研究其进展，通过使用鼠去氧肾上腺素启动子以足细胞特异性方式表达含有类似于影响人类 FSGS 家族的突变的鼠 α-actinin-4，开发了转基因小鼠模型。与显示不完全外显率的人类 ACTN4 相关 FSGS 一致，一部分转基因小鼠表现出显着的蛋白尿（18 只中有 8 只），而蛋白尿和非蛋白尿 ACTN4 突变小鼠的总体平均收缩压均升高。免疫荧光证实了突变体 α-actinin-4 的足细胞特异性表达，实时 RT-PCR 显示蛋白尿 ACTN4 突变小鼠中的 HA-ACTN4 mRNA 水平高于非蛋白尿 ACTN4 突变小鼠。只有蛋白尿小鼠表现出与人类 ACTN4 相关 FSGS 一致的组织学特征，包括节段性硬化和一些肾小球簇粘连、肾小管扩张、系膜基质扩张以及足细胞空泡化和足突融合区域。与这种足细胞损伤一致，蛋白尿的 ACTN4 突变肾脏表现出裂隙隔膜成分去氧肾上腺素的 mRNA 和蛋白质水平显着降低。这种新开发的人类 ACTN4 相关 FSGS 小鼠模型表明，突变体 α-actinin-4 引起的肌动蛋白细胞骨架失调与去氧肾上腺素支持的狭缝隔膜复合体的恶化之间存在因果关系。
Mutations in the gene encoding alpha-actinin-4 (ACTN4), an actin crosslinking protein, are associated with a form of autosomal dominant focal segmental glomerulosclerosis (FSGS). To better study its progression, a transgenic mouse model was developed by expressing murine alpha-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter. Consistent with human ACTN4-associated FSGS, which shows incomplete penetrance, a proportion of the transgenic mice exhibited significant albuminuria (8 of 18), while the overall average systolic BP was elevated in both proteinuric and non-proteinuric ACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant alpha-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with human ACTN4-associated FSGS, including segmental sclerosis and tuft adhesion of some glomeruli, tubular dilatation, mesangial matrix expansion, as well as regions of podocyte vactiolization and foot process fusion. Consistent with such podocyte damage, proteinuric ACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of human ACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant alpha-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex.