Cabrita Ines, Talbi Khaoula, Kunzelmann Karl, Schreiber Rainer
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
Cell Calcium. 2021 Apr 24;97:102413. doi: 10.1016/j.ceca.2021.102413.
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 Ca signaling. Enhanced expression of TMEM16A and Ca 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 Ca 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 Ca and augmented store-operated Ca entry, which was both independent of TMEM16A. However, disease causing purinergic Ca 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.
在多囊肾病（PKD）中，多个双侧肾囊肿逐渐增大，导致肾功能下降。通过囊性纤维化跨膜电导调节因子（CFTR）和TMEM16A（anoctamin 1）进行的跨上皮氯化物分泌驱动囊肿增大。我们最近证明，PKD1的缺失会增加小鼠肾脏和小鼠M1集合管细胞中TMEM16A的表达和功能。数据表明，TMEM16A通过上调细胞内钙信号传导，对囊肿生长起着至关重要的作用。TMEM16A和钙信号传导的增强表达增加了细胞增殖和液体分泌，这表明抑制TMEM16A可能是治疗常染色体显性多囊肾病（ADPKD）的一种新疗法。所有ADPKD病例中约15%是由PKD2突变引起的。为了分析PKD2功能丧失对钙信号传导的影响，在本研究中，我们使用shRNA的病毒转染技术，在小鼠原代肾上皮细胞中敲低Pkd2。与Pkd1-/-细胞不同，敲低PKD2会降低基础钙水平，并增强储存操纵性钙内流，这两者均独立于TMEM16A。然而，与在Pkd1-/-肾上皮细胞中观察到的情况类似，导致疾病的嘌呤能钙储存释放增强。目前的数据表明，对TMEM16A进行药理学抑制可作为治疗由PKD1和PKD2突变引起的ADPKD的一种方法。
