Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells.
Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells.
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DOI：
10.1038/s41598-018-23341-2
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发表时间：
2018-03-21
影响因子：
4.6
通讯作者：
Tran PV
中科院分区：
文献类型：
--
作者：
Silva LM;Jacobs DT;Allard BA;Fields TA;Sharma M;Wallace DP;Tran PV
常染色体显性多囊肾病 (ADPKD) 是由分别编码多囊蛋白 1 和 2 的 PKD1 或 PKD2 突变引起的。多囊蛋白定位于初级纤毛，多囊蛋白复合物的功能丧失导致肾脏中充满液体的囊肿的形成和逐渐生长。 ADPKD 的发病机制复杂，纤毛功能障碍与肾囊肿发生之间的分子机制尚不清楚。初级纤毛介导 Hedgehog 信号传导，以组织依赖性方式调节细胞增殖和分化。此前，我们发现 Hedgehog 信号在几种 PKD 小鼠模型的囊性肾中增加，并且 Hedgehog 抑制可阻止 cAMP 处理的胚胎 PKD 小鼠肾脏中囊肿的形成。在这里，我们发现在人类 ADPKD 组织中，Hedgehog 靶点和激活剂 Glioma 1 升高并定位于囊肿衬里上皮细胞和间质细胞，表明 ADPKD 中自分泌和旁分泌 Hedgehog 信号传导分别增加。此外，Hedgehog 抑制剂可减少 ADPKD 细胞的基础增殖和 cAMP 诱导的增殖以及体外囊肿形成。这些数据表明，Hedgehog 信号传导在人类 ADPKD 中增加，并且抑制 Hedgehog 信号传导可以对抗促进体外囊肿生长的细胞过程。
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutation of PKD1 or PKD2, which encode polycystin 1 and 2, respectively. The polycystins localize to primary cilia and the functional loss of the polycystin complex leads to the formation and progressive growth of fluid-filled cysts in the kidney. The pathogenesis of ADPKD is complex and molecular mechanisms connecting ciliary dysfunction to renal cystogenesis are unclear. Primary cilia mediate Hedgehog signaling, which modulates cell proliferation and differentiation in a tissue-dependent manner. Previously, we showed that Hedgehog signaling was increased in cystic kidneys of several PKD mouse models and that Hedgehog inhibition prevented cyst formation in embryonic PKD mouse kidneys treated with cAMP. Here, we show that in human ADPKD tissue, Hedgehog target and activator, Glioma 1, was elevated and localized to cyst-lining epithelial cells and to interstitial cells, suggesting increased autocrine and paracrine Hedgehog signaling in ADPKD, respectively. Further, Hedgehog inhibitors reduced basal and cAMP-induced proliferation of ADPKD cells and cyst formation in vitro. These data suggest that Hedgehog signaling is increased in human ADPKD and that suppression of Hedgehog signaling can counter cellular processes that promote cyst growth in vitro.
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