Glomerular and proximal tubule cysts as early manifestations of Pkd1 deletion
Glomerular and proximal tubule cysts as early manifestations of Pkd1 deletion
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DOI：
10.1093/ndt/gfp611
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发表时间：
2010-04-01
影响因子：
6.1
通讯作者：
Devuyst, Olivier
中科院分区：
文献类型：
--
作者：
Ahrabi, Ali K.;Jouret, Francois;Devuyst, Olivier
背景小鼠Pkd 1的纯合性缺失导致胚胎死亡，伴有肾囊肿和胎儿水肿，但关于囊肿的节段起源和与羊水过多相关的潜在变化没有精确的数据。我们使用Pkd 1基因敲除小鼠研究囊肿发生，并分析从胚胎12.5天（E12.5）到出生（n = 257个胚胎）的羊水成分。在Pkd 1（-/-）胚胎中，从E13.5开始始终观察到羊水过多，没有胎盘异常，但从E13.5到E16.5，钠和葡萄糖的排泄量显著增加，在E14.5和E15.5环腺苷酸（cAMP）水平增加。Pkd 1（-/-）胚胎在E13.5开始死亡，致死率在E15.5达到峰值，对应于囊肿发生的开始。Pkd 1（-/-）肾脏中的第一个囊肿出现在E15.5的皮质-髓质交界处的间充质来源节段中，其中大部分为肾小球囊肿，少数为近端小管囊肿（巨蛋白阳性）。从E16.5开始，囊肿延伸至输尿管芽源性集合管（扁豆凝集素阳性）。这些研究表明，Pkd 1缺失与大量溶质丢失（来自E13.5）和与羊水过多相关的cAMP水平升高（E14.5）相关。这些异常先于肾囊肿（E15.5），首先来源于肾小球和近端小管，后来来源于集合管，反映了Pkd 1在成熟上皮细胞中的表达模式。
Background. The homozygous deletion of Pkd1 in the mouse results in embryonic lethality with renal cysts and hydrops Fetal's, but there is no precise data on the segmental origin of cysts and potential changes associated with polyhydramnios.Methods. We used Pkd1-null mice to investigate cystogenesis and analyze the amniotic fluid composition from embryonic day 12.5 (E12.5) to birth (n = 257 embryos).Results. Polyhydramnios was consistently observed from E13.5 in Pkd1(-/-) embryos, in absence of placental abnormalities but with a significantly higher excretion of sodium and glucose from E13.5 through E16.5, and increased cyclic adenosine 3'5-monophosphate (cAMP) levels at E14.5 and E15.5. The Pkd1(-/-) embryos started to die at E13.5, with lethality peaking at E15.5, corresponding to the onset of cystogenesis. The first cysts in Pkd1(-/-) kidneys emerged at E15.5 in mesenchyme-derived segments at the cortico-medullary junction, with a majority of glomerular cysts and fewer proximal tubule cysts (positive for megalin). The cysts extended to ureteric bud-derived collecting ducts (positive for Dolichos biflorus agglutinin lectin) from E16.5.Conclusions. These studies indicate that Pkd1 deletion is associated with a massive loss of solutes (from E13.5) and increased cAMP levels (E14.5) associated with polyhydramnios. These abnormalities precede renal cysts (E15.5), first derived from glomeruli and proximal tubules and later from the collecting ducts, reflecting the expression pattern of Pkd1 in maturing epithelial Cells.