Noninvasive assessment of antenatal hydronephrosis in mice reveals a critical role for Robo2 in maintaining anti-reflux mechanism.
Noninvasive assessment of antenatal hydronephrosis in mice reveals a critical role for Robo2 in maintaining anti-reflux mechanism.
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对小鼠产前肤色的无创评估揭示了Robo2在维持抗反推理机制中的关键作用。
DOI：
10.1371/journal.pone.0024763
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Wang H;Li Q;Liu J;Mendelsohn C;Salant DJ;Lu W
肾盂积水和膀胱输尿管反流（VUR）是常见的出生缺陷。我们最近发现，Robo2基因的破坏与人类VUR和敲除小鼠产前肾积水有关。然而，这些临床病症的自然史、因果关系和发育起源在很大程度上仍不清楚。尽管Robo2基因敲除小鼠的肾积水表型被归因于同一小鼠中输尿管反流和梗阻的共存，但这一假设尚未得到实验验证。在这里，我们使用非侵入性的高分辨率显微超声和病理分析，以遵循个别Robo2缺陷小鼠从胚胎到成年的产前肾积水的进展。我们发现肾积水在出生后持续发展，没有自发性消退。通过使用微泡超声造影剂和超声引导下经皮穿刺抽吸，我们证明了Robo2缺陷小鼠的产前肾积水是由输尿管膀胱连接处扩张和功能不全引起的高级别VUR引起的，而不是输尿管梗阻。我们进一步记录了Robo2在发育中的输尿管膀胱连接处的表达，并将输尿管口结构的早期扩张确定为产前肾积水和VUR的潜在胎儿起源。因此，我们的研究结果表明，Robo2是至关重要的形成一个正常的输尿管口和维持一个有效的抗反流机制。本研究还建立了一个可重复的遗传小鼠模型进行性产前肾积水和原发性高级别VUR。
Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR.
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