Loss of PKD1 and PKD2 share common effects on intracellular Ca2+ signaling
Loss of PKD1 and PKD2 share common effects on intracellular Ca2+ signaling
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PKD1和PKD2的缺失在细胞内钙信号转导中的共同作用
DOI：
10.1016/j.ceca.2021.102413
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发表时间：
2021-04-27
期刊：
影响因子：
4
通讯作者：
Schreiber, Rainer
中科院分区：
文献类型：
--
作者：
Cabrita, Ines;Talbi, Khaoula;Schreiber, Rainer
多囊肾病（PKD）是一种常见的肾病综合征，其病因是多囊肾。通过囊性纤维化跨膜传导调节因子（CFTR）和TMEM 16 A（anoctamin 1）的跨上皮氯分泌驱动囊肿扩大。我们最近证明，PKD 1的损失增加了小鼠肾脏和小鼠M1集合管细胞中TMEM 16 A的表达和功能。数据表明，TMEM 16 A通过上调细胞内Ca 2+信号传导基本上有助于囊肿生长。TMEM 16 A和Ca 2+信号的增强表达增加了细胞增殖和液体分泌，这表明抑制TMEM 16 A作为ADPKD的新疗法。大约15%的ADPKD病例是由PKD 2突变引起的。为了分析PKD 2功能丧失对Ca 2+信号传导的影响，我们在本研究中使用病毒转染shRNA敲低小鼠原代肾上皮细胞中的Pkd 2。与Pkd 1-/-细胞不同，PKD 2的敲除降低了基础Ca 2+和增强了钙库操作的Ca 2+内流，这两者都不依赖于TMEM 16 A。然而，引起疾病的嘌呤能Ca 2+储存释放增强，类似于在Pkd 1-/-肾上皮细胞中观察到的。目前的数据表明TMEM 16 A作为PKD 1和PKD 2突变引起的ADPKD治疗的药理学抑制。
In polycystic kidney disease (PKD) multiple bilateral renal cysts gradually enlarge causing a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) drive cyst enlargement. We demonstrated recently that a loss of PKD1 increases expression and function of TMEM16A in murine kidneys and in mouse M1 collecting duct cells. The data demonstrated that TMEM16A contributes essentially to cyst growth by upregulating intracellular Ca2+ signaling. Enhanced expression of TMEM16A and Ca2+ signaling increased both cell proliferation and fluid secretion, which suggested inhibition of TMEM16A as a novel therapy in ADPKD. About 15 % of all ADPKD cases are caused by mutations in PKD2. To analyze the effects of loss of function of PKD2 on Ca2+ signaling, we knocked-down Pkd2 in mouse primary renal epithelial cells in the present study, using viral transfection of shRNA. Unlike in Pkd1-/- cells, knockdown of PKD2 lowered basal Ca2+ and augmented store-operated Ca2+ entry, which was both independent of TMEM16A. However, disease causing purinergic Ca2+ store release was enhanced, similar to that observed in Pkd1-/- renal epithelial cells. The present data suggest pharmacological inhibition of TMEM16A as a treatment in ADPKD caused by mutations in both PKD1 and PKD2.