Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD.
Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD.
复制标题
ADPKD Pkd2WS25/- 小鼠模型肾囊性上皮的组织病理学分析。
DOI：
10.1152/ajprenal.00153.2003
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Aronson,PeterS
中科院分区：
文献类型：
--
作者：
Thomson,RBrent;Mentone,SueAnn;Kim,Robert;Earle,Karen;Delpire,Eric;Somlo,Stefan;Aronson,PeterS
常染色体显性遗传性多囊肾病(ADPKD)是一种常染色体显性遗传性多囊肾病(ADPKD)，常染色体显性遗传性多囊肾病(ADPKD)影响的肾上皮细胞在发生囊变过程中经历了从高分化的吸收状态到低分化的分泌状态的表型转变，这种转变伴随着上皮细胞极性的丧失和特定膜蛋白的错误定位。我们在ADPKD的Pkd2WS25/-小鼠模型中对这一假说进行了详细的评估。Pkd2WS25/-包囊的超微结构分析证实，随着包囊增大，包囊上皮细胞逐渐去分化。用针对Na+-K+-ATPase、KSP-cadherin和E-cadherin的抗体对早期和晚期的囊肿进行免疫细胞化学分析，均未能检测到囊细胞极性改变的证据。Na+-K+-ATPase和KSP-cadherin仅在所有早期囊性病变的上皮细胞基底膜(BLM)上表达。Na+-K+-ATPase和KSP-钙粘蛋白的表达水平均随细胞去分化程度的增加而递减，但两者均未发生错位定位。高度去分化的囊肿不表达免疫检测水平的Na+-K+-ATPase或KSP-钙粘蛋白。E-钙粘附素在所有囊性病变的上皮层均有显著表达。随后，用针对Na+-K+-Cl-共转运体NKCC1分泌异构体的抗体对包囊进行染色。NKCC1的表达仅见于晚期囊肿组。我们的数据与进行性囊性上皮细胞去分化模型一致，在该模型中，晚期囊液的积聚是通过跨上皮分泌氯化物而不是通过顶端Na+-K+-ATPase分泌钠来实现的。
It has been proposed that autosomal dominant polycystic kidney disease (ADPKD)affected renal epithelial cells undergo a phenotypic transition from a highly differentiated absorptive state to a much less differentiated secretory state during cystogenesis and that this transition is accompanied by loss of epithelial cell polarity and mistargeting of specific membrane proteins. We conducted a detailed evaluation of this hypothesis in thePkd2WS25/-mouse model of ADPKD. Ultrastructural analysis ofPkd2WS25/-cysts by electron microscopy confirmed that cystic epithelial cells progressively dedifferentiate with cyst enlargement. Immunocytochemical analysis of both early- and late-stage cysts with antibodies directed against Na+-K+-ATPase, Ksp-cadherin, and E-cadherin failed to detect evidence of altered cyst cell polarity. Na+-K+-ATPase and Ksp-cadherin were expressed exclusively on the basolateral membranes (BLM) of epithelial cells in all early cysts. Expression levels of both Na+-K+-ATPase and Ksp-cadherin decreased progressively with the degree of cyst cell dedifferentiation, but neither protein was ever mislocalized. Highly dedifferentiated cysts did not express immunodetectable levels of either Na+-K+-ATPase or Ksp-cadherin. E-cadherin was expressed prominently on the BLM of all cysts. Cysts were subsequently stained with an antibody directed against the secretory isoform of the Na+-K+-Cl-cotransporter NKCC1. NKCC1 expression was detected on the BLM of advanced cysts only. Our data are consistent with a model of progressive cystic epithelial cell dedifferentiation in which fluid accumulation in late-stage cysts is mediated by transepithelial secretion of chloride rather than secretion of sodium by apical Na+-K+-ATPase.