Institute for Translational Neurology and Neurology Clinic, University of Muenster, Muenster, Germany.
Department of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
Cell Mol Gastroenterol Hepatol. 2022;14(6):1199-1211. doi: 10.1016/j.jcmgh.2022.08.003. Epub 2022 Aug 13.
BACKGROUND & AIMS: The 2-pore potassium channel subfamily K member 9 (KCNK9) regulates intracellular calcium concentration and thus modulates cell survival and inflammatory signaling pathways. It also was recognized as a risk allele for inflammatory bowel disease. However, it remains unclear whether KCNK9 modulates inflammatory bowel disease via its impact on immune cell function or whether its influence on calcium homeostasis also is relevant in intestinal epithelial cells.
Kcnk9 mice were challenged with 3% dextran sulfate sodium (DSS) to induce experimental acute colitis. Primary cultures of intestinal epithelial cells were generated, and expression of potassium channels as well as cytosolic calcium levels and susceptibility to apoptosis were evaluated. Furthermore, we evaluated whether KCNK9 deficiency was compensated by the closely related 2-pore potassium channel KCNK3 in vivo or in vitro.
Compared with controls, KCNK9 deficiency or its pharmacologic blockade were associated with aggravated DSS-induced colitis compared with wild-type animals. In the absence of KCNK9, intestinal epithelial cells showed increased intracellular calcium levels and were more prone to mitochondrial damage and caspase-9-dependent apoptosis. We found that expression of KCNK3 was increased in Kcnk9 mice but did not prevent apoptosis after DSS exposure. Conversely, increased levels of KCNK9 in Kcnk3 mice were associated with an ameliorated course of DSS-induced colitis.
KCNK9 enhances mitochondrial stability, reduces apoptosis, und thus supports epithelial cell survival after DSS exposure in vivo and in vitro. Conversely, its increased expression in Kcnk3 resulted in less mitochondrial damage and apoptosis and was associated with beneficial outcomes in DSS-induced colitis.
双孔钾通道亚家族 K 成员 9（KCNK9）调节细胞内钙离子浓度，从而调节细胞存活和炎症信号通路。它也被认为是炎症性肠病的风险等位基因。然而，目前尚不清楚 KCNK9 是否通过影响免疫细胞功能或通过其对钙稳态的影响来调节炎症性肠病，以及其对钙稳态的影响是否与肠上皮细胞有关。
用 3%葡聚糖硫酸钠（DSS）对 Kcnk9 小鼠进行攻击，以诱导实验性急性结肠炎。生成肠上皮细胞原代培养物，并评估钾通道的表达以及细胞浆钙离子水平和易感性凋亡。此外，我们评估了体内或体外 KCNK3 对 KCNK9 缺乏的补偿作用。
与对照组相比，与野生型动物相比，KCNK9 缺乏或其药理学阻断与 DSS 诱导的结肠炎加重有关。在缺乏 KCNK9 的情况下，肠上皮细胞显示出增加的细胞内钙离子水平，并且更容易发生线粒体损伤和 caspase-9 依赖性细胞凋亡。我们发现，在 Kcnk9 小鼠中，KCNK3 的表达增加，但在 DSS 暴露后不能预防细胞凋亡。相反，在 Kcnk3 小鼠中增加的 KCNK9 水平与 DSS 诱导的结肠炎的改善病程有关。
KCNK9 增强了线粒体的稳定性，减少了凋亡，从而支持了体内和体外 DSS 暴露后上皮细胞的存活。相反，其在 Kcnk3 中的表达增加导致线粒体损伤和凋亡减少，并与 DSS 诱导的结肠炎的有益结果相关。
