Mechanisms of the proteinuria induced by Rho GTPases.
Mechanisms of the proteinuria induced by Rho GTPases.
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DOI：
10.1038/ki.2011.472
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发表时间：
2012-06
影响因子：
19.6
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中科院分区：
文献类型：
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足细胞是高度分化的细胞，在维持肾小球滤过屏障的完整性方面发挥着重要作用；这一功能受Rho家族的小GTP酶蛋白调节。为了研究Rho A在足细胞生物学中的作用，我们建立了在足细胞中表达多西环素可诱导成分活性(V14Rho)或显性阴性Rho A(N19Rho)的转基因小鼠。足细胞中Rho A结构的特异性诱导导致蛋白尿和足突消失，肌动蛋白相关蛋白synaptopodin的表达减少证明了肌动蛋白细胞骨架的破坏。然而，这些不利影响的机制似乎是不同的。活化的V14Rho可促进肌动蛋白聚合，降低newitin的mRNA和蛋白水平，促进足细胞凋亡，降低内源性Rho A水平。相反，显性阴性的N19Rho导致足细胞应激纤维的丢失，不改变neparin或Rho A的表达，也不引起足细胞凋亡。因此，我们的研究结果表明，在基础状态下，Rho A在维持肾小球滤过屏障的完整性方面起着重要作用，但基础水平以上的Rho A活性增强会促进足细胞损伤。
Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14Rho) or dominant-negative Rho A (N19Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.