Activation of RhoA in Podocytes Induces Focal Segmental Glomerulosclerosis
Activation of RhoA in Podocytes Induces Focal Segmental Glomerulosclerosis
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DOI：
10.1681/asn.2010111146
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发表时间：
2011-09-01
影响因子：
13.6
通讯作者：
Takano, Tomoko
中科院分区：
文献类型：
--
作者：
Zhu, Lei;Jiang, Ruihua;Takano, Tomoko
肌动蛋白骨架的正常组织对足细胞的正常结构和功能至关重要。RhoA调节肌动蛋白动力学，但其在足细胞生物学中的作用是有争议的。在这里，我们产生了转基因小鼠，以足细胞特异性和强力霉素诱导的方式表达RhoA的组成活性形式。强力霉素诱导活化RhoA导致明显的蛋白尿。此外，蛋白尿的程度和肾小球的组织学改变都与RhoA的组成性活性表达水平呈正相关：低水平的表达与节段性足过程消失相关，光镜下观察不到变化，而高水平的表达与广泛的足过程消失和局灶节段性肾小球硬化（FSGS）的组织学特征相关。此外，激活RhoA诱导的肾小球纤维连接蛋白和胶原IA1 mRNA表达显著上调，且上调程度与蛋白尿水平呈正相关。在大多数小鼠中，停用强力霉素导致蛋白尿下降到基础水平，但在一些小鼠中，重度蛋白尿持续存在。综上所述，这些数据表明足细胞中RhoA的激活可导致蛋白尿，并伴有人类微小变化病和FSGS的一系列组织学变化。虽然大多数改变是可逆的，但严重和长期的RhoA激活可能导致不可逆的肾小球硬化。
Proper organization of the actin cytoskeleton is essential for the normal structure and function of podocytes. RhoA modulates actin dynamics but its role in podocyte biology is controversial. Here, we generated transgenic mice that express a constitutively active form of RhoA in a podocyte-specific and doxycycline-inducible manner. Induction of activated RhoA with doxycycline resulted in significant albuminuria. Furthermore, both the degree of albuminuria and the histologic changes in the glomerulus positively correlated with the level of constitutively active RhoA expression: low levels of expression associated with segmental foot-process effacement without changes observable by light microscopy, whereas higher levels of expression associated with both extensive foot-process effacement and histologic features of focal segmental glomerulosclerosis (FSGS). In addition, induction of activated RhoA markedly upregulated glomerular mRNA expression of fibronectin and collagen IA1, and the degree of upregulation positively correlated with the level of albuminuria. Withdrawal of doxycycline led to a decline in albuminuria toward basal levels in most mice, but heavy albuminuria persisted in some mice. Taken together, these data suggest that activation of RhoA in podocytes leads to albuminuria accompanied by a range of histologic changes characteristic of minimal change disease and FSGS in humans. Although most changes are reversible, severe and prolonged activation of RhoA may cause irreversible glomerulosclerosis.