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.

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器 (CFTR) 和 TMEM16A (anoctamin 1) 的跨上皮氯分泌驱动囊肿扩大。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 主要通过上调细胞内 Ca ²⁺信号传导来促进囊肿生长。 TMEM16A 和 Ca ²⁺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 可作为 ADPKD 的新疗法。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 Ca ²⁺信号传导的影响，我们在本研究中使用 shRNA 病毒转染敲低了小鼠原代肾上皮细胞中的Pkd2 。与Pkd1-/-细胞不同，PKD2 的敲低降低了基础 Ca ²⁺并增加了钙池操作的 Ca ²⁺进入，这两者均独立于 TMEM16A。然而，引起嘌呤能Ca ²⁺储存释放的疾病增强，类似于在Pkd1-/-肾上皮细胞中观察到的情况。目前的数据表明，TMEM16A 作为治疗由PKD1和PKD2突变引起的 ADPKD 的药理抑制作用。