Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways
Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways
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DOI：
10.1093/hmg/ddp190
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发表时间：
2009-07-15
影响因子：
3.5
通讯作者：
Peters, Dorien J. M.
中科院分区：
文献类型：
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作者：
Happe, Hester;Leonhard, Wouter N.;Peters, Dorien J. M.
常染色体显性遗传性多囊肾病（ADPKD）的特征是巨大的充满液体的囊肿和肾功能进行性恶化，需要肾脏替代治疗。以前，我们产生了一个他莫昔芬诱导的，肾上皮特异性Pkd 1缺失的小鼠模型，并表明Pkd 1基因的失活诱导快速囊肿形成在发育中的肾脏和疾病的发病缓慢的成年小鼠。因此，我们假设损伤诱导的肾小管上皮细胞增殖可能会加速成年Pkd 1缺失小鼠肾脏囊肿的形成。在Pkd 1基因失活后，用肾毒性物质1，2-二氯乙烯基半胱氨酸（DCVC）处理小鼠，这确实显著加速了囊肿形成。在组织再生过程中增殖增加后，Pkd 1缺失小鼠的增殖下降到基础水平，就像DCVC处理的对照组一样。然而，在严重的囊性肾中，损伤后10-14周，增殖再次增加。这种双相反应表明，损伤后不受限制的细胞增殖不是囊肿形成的潜在机制。异常的平面细胞极性（PCP）信号传导和增加的经典Wnt信号传导被认为参与囊肿形成。事实上，我们在这里表明，在Pkd 1条件性缺失小鼠的PCP组件四关节（Fjx 1）的表达减少，而其表达是组织再生过程中所需的。此外，我们发现，改变中心体的位置和激活典型的Wnt信号的早期影响Pkd 1基因中断。这表明需要额外的刺激或事件来触发囊肿形成的过程。我们建议，在组织修复过程中，新形成的Pkd 1缺陷细胞的完整性被修改，使它们容易受到随后的囊肿形成。
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by large fluid-filled cysts and progressive deterioration of renal function necessitating renal replacement therapy. Previously, we generated a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model and showed that inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Therefore, we hypothesized that injury-induced tubular epithelial cell proliferation may accelerate cyst formation in the kidneys of adult Pkd1-deletion mice. Mice were treated with the nephrotoxicant 1,2-dichlorovinyl-cysteine (DCVC) after Pkd1-gene inactivation, which indeed accelerated cyst formation significantly. After the increased proliferation during tissue regeneration, proliferation decreased to basal levels in Pkd1-deletion mice just as in DCVC-treated controls. However, in severe cystic kidneys, 10-14 weeks after injury, proliferation increased again. This biphasic response suggests that unrestricted cell proliferation after injury is not the underlying mechanism for cyst formation. Aberrant planar cell polarity (PCP) signaling and increased canonical Wnt signaling are suggested to be involved in cyst formation. Indeed, we show here that in Pkd1 conditional deletion mice expression of the PCP component Four-jointed (Fjx1) is decreased while its expression is required during tissue regeneration. In addition, we show that altered centrosome position and the activation of canonical Wnt signaling are early effects of Pkd1-gene disruption. This suggests that additional stimuli or events are required to trigger the process of cyst formation. We propose that during tissue repair, the integrity of the newly formed Pkd1-deficient cells is modified rendering them susceptible to subsequent cyst formation.