Department 2 of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
J Mol Med (Berl). 2013 Jun;91(6):739-48. doi: 10.1007/s00109-013-1000-x. Epub 2013 Jan 24.
MicroRNAs have emerged as essential regulators of gene expression and may play important roles in a variety of human disorders. To understand the role of microRNA-mediated gene regulation in the kidney, we deleted the microRNA-processing enzyme Dicer in developing renal tubules and parts of the ureteric bud in mice. Genetic deletion of Dicer resulted in renal failure and death of the animals at 4-6 weeks of age. Interestingly, the kidneys of microRNA-deficient animals were small due to a reduced number of nephrons and showed massive hydronephrosis due to ureteropelvic junction obstruction. This phenotype is reminiscent of congenital anomalies of the kidney and urinary tract (CAKUT), an important group of human disorders characterized by a combination of renal hypoplasia with congenital abnormalities of the urinary tract. We used metanephric kidney cultures to examine the developmental defects underlying these pathologies. Dicer knockout kidneys showed a significant reduction of tubular branching explaining renal hypoplasia. Moreover, the ureters of these kidneys showed an altered morphology and impaired motility. These functional changes went along with altered expression of smooth muscle actin implying a defect in the differentiation of ureteric smooth muscle cells. In addition, we show the polycystic kidney disease gene Pkd1 to be a target of miR-20 implying that this interaction may contribute to the molecular basis for the cystogenesis in our model. In conclusion, these data demonstrate an essential role for microRNA-dependent gene regulation in mammalian kidney development and suggest that deregulation of microRNAs may underlie CAKUT, the most important group of renal disorders in humans.
微小 RNA 已成为基因表达的重要调控因子，可能在多种人类疾病中发挥重要作用。为了了解微小 RNA 介导的基因调控在肾脏中的作用，我们在发育中的肾小管和输尿管芽的部分中敲除了微小 RNA 加工酶 Dicer 的基因。Dicer 的基因缺失导致肾脏衰竭，动物在 4-6 周龄时死亡。有趣的是，微小 RNA 缺陷动物的肾脏由于肾单位数量减少而较小，并由于输尿管肾盂连接部梗阻而出现大量肾盂积水。这种表型类似于先天性肾和泌尿道异常（CAKUT），这是一组重要的人类疾病，其特征是肾发育不全与泌尿道先天性异常的组合。我们使用后肾原基肾培养物来检查这些病变背后的发育缺陷。Dicer 敲除肾脏的管状分支显著减少，解释了肾发育不全。此外，这些肾脏的输尿管表现出异常的形态和运动功能障碍。这些功能变化伴随着平滑肌肌动蛋白表达的改变，表明输尿管平滑肌细胞的分化存在缺陷。此外，我们还证明多囊肾病基因 Pkd1 是 miR-20 的靶基因，这表明这种相互作用可能有助于我们模型中囊肿发生的分子基础。总之，这些数据表明微小 RNA 依赖的基因调控在哺乳动物肾脏发育中起着至关重要的作用，并表明微小 RNA 的失调可能是 CAKUT 的基础，CAKUT 是人类最重要的一组肾脏疾病。
