Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan; Section of Biological Science, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Japan.
Am J Pathol. 2018 Sep;188(9):2120-2138. doi: 10.1016/j.ajpath.2018.05.011. Epub 2018 Jun 20.
The distal tubule (DT) helps regulate blood pressure and electrolytes. We describe a novel, autosomal recessive, morphofunctional DT abnormality in inbred mice evident as columnar alternations and age-related cystic changes. This abnormality developed in both sexes of DBA/2Cr. Similar phenotypes were observed in A/J, C3H/He, DBA/1J, and FVB/N strains, but not in AKR/N, BALB/c, or C57BL/6N strains. In DBA/2Cr, abnormal DT localized to straight and convoluted segments and showed IL-36α DT injury marker expression. However, DT epithelial proliferation, examined by bromodeoxyuridine incorporation, was not remarkably altered with the progression of abnormality. Abnormal DT epithelial cells in DBA/2Cr displayed elongated primary cilia, loose intercellular adhesions, and numerous vesicles with altered localization of CD9, Na/KATPase, and E-cadherin, indicating altered cell function, adhesion, and polarity. DBA/2Cr-type D12Mit182-D12Mit83 was identified as a candidate locus designated DBA/2 renal cyst (drecy). Within drecy, the gene regulated by estrogen in breast cancer protein (Greb1) transcript variant 2 was significantly up-regulated in DBA/2Cr kidney versus C57BL/6N. Greb1 localized to DT cytoplasm in C57BL/6 and to cytoplasm and nucleus in DBA/2Cr. Greb1-overexpressing M-1 kidney cells showed an altered epithelial-mesenchyme phenotype. B6.D2-(D12Mit182-D12Mit83) congenic mice carrying drecy did not show DT abnormalities, whereas DBA/2Cr × B6.D2-(D12Mit182-D12Mit83) mice did. Identification of this novel DT abnormality regulated by a DBA/2Cr mouse chromosome 12-derived locus and additional genetic factors improve the understanding of DT pathogenesis.
远曲小管（DT）有助于调节血压和电解质。我们描述了一种新型的常染色体隐性遗传的形态功能 DT 异常，这种异常在近交系小鼠中表现为柱状交替和与年龄相关的囊性改变。这种异常在 DBA/2Cr 的雌雄两性中均有发生。在 A/J、C3H/He、DBA/1J 和 FVB/N 品系中观察到类似的表型，但在 AKR/N、BALB/c 或 C57BL/6N 品系中没有观察到。在 DBA/2Cr 中，异常的 DT 定位于直段和卷曲段，并显示出 IL-36α DT 损伤标志物的表达。然而，通过溴脱氧尿苷掺入检测到的 DT 上皮细胞增殖在异常进展过程中并没有明显改变。DBA/2Cr 中异常的 DT 上皮细胞表现出伸长的初级纤毛、细胞间连接松散和大量囊泡，其 CD9、Na/KATPase 和 E-钙粘蛋白的定位发生改变，表明细胞功能、黏附和极性发生改变。DBA/2Cr 型 D12Mit182-D12Mit83 被鉴定为一个候选基因座，命名为 DBA/2 肾囊肿（drecy）。在 drecy 内，雌激素调节的乳腺癌蛋白（Greb1）转录变体 2 的基因在 DBA/2Cr 肾脏中的表达明显高于 C57BL/6N。Greb1 在 C57BL/6 中定位于 DT 细胞质，在 DBA/2Cr 中定位于细胞质和细胞核。过表达 Greb1 的 M-1 肾细胞表现出上皮-间充质表型改变。携带 drecy 的 B6.D2-（D12Mit182-D12Mit83）近交系小鼠没有出现 DT 异常，而 DBA/2Cr×B6.D2-（D12Mit182-D12Mit83）小鼠则出现了这种异常。这种新型 DT 异常的鉴定受 DBA/2Cr 小鼠 12 号染色体来源的基因座和其他遗传因素的调节，这提高了我们对 DT 发病机制的理解。
