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Development of congenital anomalies of the kidney and urinary tract (CAKUT)

肾脏和泌尿道先天性异常 (CAKUT) 的发展

基本信息

批准号：
12307021
负责人：
ICHIKAWA Iekuni
金额：
$ 27.76万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12307021/
关键词：
BMP4 Foxc1 CAKUT kidney urinary tract development renal hypoplasia mouse

项目摘要

It has been postulated that ectopia of the initial ureter budding is the first ontogenic misstep that leads to many congenital anomalies of the kidney and urinary tract (CAKUT). The ectopia can result in hypoplastic kidney, ectopia of ureterovesical orifice, urinary outflow obstruction and/or reflux. Our studies on several mutant mouse models, e.g., Bmp4 +/-, Foxc1 -/-, Agtr2 -/Y, verified that ectopic ureter budding indeed occurs prior to the formation of CAKUT. Moreover we found that BMP4, acting on the Wolffian duct and ureter epithelium, determines the budding site of the ureter by locally antagonizing ubiquitous inductive signal(s) from the metanephric mesenchyme. However, analyses of Foxc1 -/-revealed that, whereas ectopic ureter can result in hypoplastic kidney and ureter morphological abnormality, it cannot cause formation of multicystic dysplastic kidney, a well-known renal abnormality seen in human CAKUT. Often, the genes involved in navigating the site of ureteral budding also regulate later ontogenic processes of the kidney and other urinary tract system. For example, BMP4 has multiple biological' functions during kidney and urinary tract formation as follows. In addition to determining budding site of the ureter, BMP4 (1) stimulates elongation of the budding ureter, 2) promotes growth of the metanephric mesenchyme by inhibiting apoptosis, and 3) has a role on the formation of glomerular tuft during glomerulogenesis. Thus, these additional functions of the genes underlie the wide spectrum of CAKUT, as the genes are expressed at multiple sites at multiple ontogenic stages, and regulate the morphogenesis of the many portions Qf the excretory system through their distinctive cellular functions.

据推测，初始输尿管出芽的异位是导致许多肾脏和泌尿道先天性异常（CAKUT）的第一个个体错误。异位可导致肾脏发育不全、输尿管膀胱口异位、尿流梗阻和/或反流。我们对几种突变小鼠模型（例如 Bmp4 +/-、Foxc1 -/-、Agtr2 -/Y）的研究证实，异位输尿管出芽确实发生在 CAKUT 形成之前。此外，我们发现BMP4作用于沃尔夫管和输尿管上皮，通过局部拮抗来自后肾间质的普遍存在的感应信号来确定输尿管的出芽部位。然而，对 Foxc1 -/- 的分析表明，虽然异位输尿管可导致肾发育不全和输尿管形态异常，但它不会导致多囊性发育不良肾的形成，这是一种在人类 CAKUT 中常见的肾脏异常。通常，参与输尿管出芽部位导航的基因也调节肾脏和其他泌尿道系统的后期个体发育过程。例如，BMP4在肾脏和尿路形成过程中具有如下多种生物学功能。除了确定输尿管的出芽位置外，BMP4 (1) 刺激出芽输尿管的伸长，2) 通过抑制细胞凋亡促进后肾间质的生长，3) 在肾小球发生过程中对肾小球簇的形成发挥作用。因此，基因的这些附加功能构成了广泛的 CAKUT 谱，因为这些基因在多个个体发育阶段的多个位点表达，并通过其独特的细胞功能调节排泄系统许多部分的形态发生。