Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.
Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.
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DOI：
10.1681/asn.2018121274
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发表时间：
2019-08
期刊：
影响因子：
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通讯作者：
Ming Ma;E. Legué;X. Tian;S. Somlo;K. Liem
中科院分区：
文献类型：
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作者：
Ming Ma;E. Legué;X. Tian;S. Somlo;K. Liem
PKD 1或PKD 2是常染色体显性多囊肾病（ADPKD）的两个主要致病基因，分别编码多囊蛋白1（PC1）和多囊蛋白2（PC2）。多囊蛋白定位于初级纤毛，一种细胞信号传导所必需的细胞器，包括刺猬途径的信号转导。在纤毛基因的突变，建立和维持纤毛也导致肾囊肿通过未知的途径。虽然最近的研究发现ADPKD相关模型和组织中Hedgehog信号的改变，但Hedgehog和多囊肾疾病之间的关系尚不清楚。方法为了研究细胞自主Hedgehog信号在ADPKD早期和成年发病小鼠模型体内调节肾囊肿形成中的潜在作用，我们在肾上皮细胞中使用Pkd1的条件性失活结合Hedgehog信号组分的条件性调节，其中Pkd1突变启动囊肿形成。在经历Pkd1失活的细胞中增加或减少Hedgehog信号传导水平后，我们评估了这些遗传操作对多囊肾疾病严重程度定量参数的影响。结果我们发现，在Pkd 1条件突变小鼠肾脏中，无论是下调还是激活沿沿着肾单位的上皮细胞中的Hedgehog通路，都不会显著影响发育或成年发病的ADPKD小鼠模型中多囊肾表型的严重程度。结论：这些数据表明，Pkd 1功能的丧失导致肾囊肿通过不受Hedgehog通路活性影响的通路。
BACKGROUND PKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known. METHODS To examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity. RESULTS We found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD. CONCLUSIONS These data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.