Wagner Kay-Dietrich, Wagner Nicole, Guo Jian-Kan, Elger Marlies, Dallman Margaret J, Bugeon Laurence, Schedl Andreas
INSERM U636, Nice, France.
Curr Biol. 2006 Apr 18;16(8):793-800. doi: 10.1016/j.cub.2006.02.072.
Pax2 is a transcription factor with important functions during kidney development . Ectopic expression of Pax2 in podocytes has been reported in various glomerular diseases , but the functional relevance remains unknown. We developed an inducible mouse model that allows activation of Pax2 specifically in podocytes. Persistent expression of Pax2 did not interfere with the initial differentiation of podocytes, but mice ectopically expressing PAX2 developed end-stage renal failure soon after birth. Similarly, activation of PAX2 in healthy adult animals resulted in renal disease within 3 weeks after podocyte-specific induction of a deleter Cre. PAX2 activation caused repression of the podocyte key regulator molecule Wt1 and consequently a dramatic reduction of nephrin expression. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. Finally, treatment of mice with an angiotensin-converting enzyme (ACE) inhibitor normalized renal function and induced upregulation of the important structural molecule nephrin via a Wt1-independent pathway. Our data demonstrate the functional significance of PAX2 reexpression in mature podocytes for the development of glomerular diseases and suggest that reactivation of PAX genes in terminally differentiated cells leads to a more dedifferentiated phenotype.
Pax2是一种在肾脏发育过程中具有重要功能的转录因子。在各种肾小球疾病中，已报道Pax2在足细胞中异位表达，但其功能相关性仍不清楚。我们构建了一种诱导性小鼠模型，可在足细胞中特异性激活Pax2。Pax2的持续表达并不干扰足细胞的初始分化，但异位表达PAX2的小鼠在出生后不久就发展为终末期肾衰竭。同样，在健康成年动物中激活PAX2，在足细胞特异性诱导deleter Cre后3周内导致肾脏疾病。PAX2激活导致足细胞关键调节分子Wt1的抑制，从而使nephrin表达显著降低。招募与groucho相关的蛋白TLE4可能参与将Pax2转化为Wt1的转录抑制因子。最后，用血管紧张素转换酶（ACE）抑制剂治疗小鼠可使肾功能恢复正常，并通过一条不依赖Wt1的途径诱导重要结构分子nephrin的上调。我们的数据证明了成熟足细胞中PAX2重新表达在肾小球疾病发展中的功能意义，并表明终末分化细胞中PAX基因的重新激活导致更去分化的表型。
