Phillips Carrie L, Miller Karen J, Filson Adele J, Nürnberger Jens, Clendenon Jeffrey L, Cook Gregory W, Dunn Kenneth W, Overbeek Paul A, Gattone Vincent H, Bacallao Robert L
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5188, USA.
J Am Soc Nephrol. 2004 Jul;15(7):1744-55. doi: 10.1097/01.asn.0000131520.07008.b3.
Cystic kidney disease has been linked to mutations in the Invs gene in mice with inversion of embryonic turning (inv/inv) and the INVS (NPHP2) gene in infants with nephronophthisis type 2 (NPHP2). The inv mouse model features multiorgan defects including renal cysts, altered left-right laterality, and hepatobiliary duct malformations transmitted in an autosomal recessive manner. Affected mice usually die of renal and liver failure by postnatal day 7. Although cardiopulmonary and liver anomalies have been carefully detailed, renal cysts have yet to be fully characterized in inv/inv. By use of three-dimensional visualization by two-photon microscopy, this study provides the first comprehensive analysis of in situ cyst formation and progression in inv/inv kidneys. At embryonic day 15, there is dilatation of Bowman's capsule followed temporally by corticomedullary cysts involving collecting ducts, proximal tubules, and thick ascending limbs. Collecting ducts of newborn inv/inv mice are uniformly and diffusely cystic from medulla to cortex, with normal diameters found only at their most proximal tips. Proximal tubules form fusiform cysts that alternate with segments of normal or narrowed caliber along torturous convolutions. Because defective cilia have been linked to situs inversus and cystogenesis, we examined inv/inv cilia by scanning and transmission electron microscopy. The former detected monocilia of expected length in cystic collecting ducts and proximal tubules; the latter demonstrated the usual 9 + 2 pattern in respiratory cilia. The inv mutant mouse has renal cysts resembling infantile NPHP2 and will provide broader insight into the role cilia play in renal cystogenesis.
多囊肾病与胚胎旋转倒置（inv/inv）小鼠的Invs基因以及2型肾单位肾痨（NPHP2）婴儿的INVS（NPHP2）基因的突变有关。inv小鼠模型具有多器官缺陷，包括肾囊肿、左右不对称改变以及常染色体隐性遗传的肝胆管畸形。受影响的小鼠通常在出生后第7天死于肾衰竭和肝衰竭。尽管心肺和肝脏异常已得到详细描述，但inv/inv小鼠的肾囊肿尚未得到充分表征。通过双光子显微镜进行三维可视化，本研究首次对inv/inv小鼠肾脏原位囊肿的形成和进展进行了全面分析。在胚胎第15天，鲍曼囊扩张，随后是涉及集合管、近端小管和髓袢升支粗段的皮质髓质囊肿。新生inv/inv小鼠的集合管从髓质到皮质均一且弥漫性囊肿化，仅在其最近端尖端发现正常直径。近端小管形成梭形囊肿，沿着曲折的盘绕与正常或狭窄管径的节段交替出现。由于缺陷纤毛与内脏反位和囊肿形成有关，我们通过扫描和透射电子显微镜检查了inv/inv小鼠的纤毛。前者在囊肿性集合管和近端小管中检测到预期长度的单纤毛；后者在呼吸道纤毛中显示出通常的9+2模式。inv突变小鼠具有类似于婴儿NPHP2的肾囊肿，将为纤毛在肾囊肿形成中的作用提供更广泛的见解。
