Sims-Lucas Sunder, Caruana Georgina, Dowling John, Kett Michelle M, Bertram John F
Department of Anatomy and Developmental Biology, Monash University, Melbourne 3800, Australia.
Pediatr Res. 2008 Jun;63(6):607-12. doi: 10.1203/PDR.0b013e31816d9130.
Several members of the transforming growth factor-beta (TGF-beta) superfamily play key roles in kidney development, either directly or indirectly regulating nephron number. Although low nephron number is a risk factor for cardiovascular and renal disease, the implications of increased nephron number has not been examined due to the absence of appropriate animal models. Here, using unbiased stereology we demonstrated that kidneys from TGF-beta2 heterozygous (TGF-beta2(+/-)) mice have approximately 60% more nephrons than wild-type mice at postnatal day 30. To determine whether augmented nephron number involved accelerated ureteric branching morphogenesis, embryonic day 11.5 metanephroi were analyzed via confocal microscopy. A 40% increase in total ureteric branch length was observed in TGF-beta2(+/-) kidneys, together with an extra generation of branching. In embryonic day 12.5 metanephroi cultured for 48 h the numbers of both ureteric tree tips and glomeruli were significantly greater in TGF-beta2(+/-) kidneys. These findings suggest that augmented nephron number in TGF-beta2(+/-) kidneys results from accelerated ureteric branching morphogenesis and nephron formation. Manipulation of TGF-beta2 signaling in vivo may provide avenues for protection or rescue of nephron endowment in fetuses at risk.
转化生长因子-β（TGF-β）超家族的多个成员在肾脏发育中发挥关键作用，直接或间接调节肾单位数量。尽管肾单位数量少是心血管和肾脏疾病的一个危险因素，但由于缺乏合适的动物模型，肾单位数量增加的影响尚未得到研究。在此，我们使用无偏倚的体视学方法证明，在出生后第30天，TGF-β2杂合子（TGF-β2(+/-)）小鼠的肾脏肾单位数量比野生型小鼠多约60%。为了确定增加的肾单位数量是否涉及输尿管分支形态发生加速，通过共聚焦显微镜分析了胚胎第11.5天的后肾。在TGF-β2(+/-)小鼠的肾脏中，观察到输尿管总分支长度增加了40%，同时出现了额外一代的分支。在培养48小时的胚胎第12.5天的后肾中，TGF-β2(+/-)小鼠肾脏的输尿管树尖端和肾小球数量均显著增加。这些发现表明，TGF-β2(+/-)小鼠肾脏中肾单位数量的增加是输尿管分支形态发生和肾单位形成加速的结果。体内操纵TGF-β2信号通路可能为保护或挽救有风险胎儿的肾单位禀赋提供途径。
