Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis.
Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis.
复制标题
维生素 D 受体通过抑制肠隐窝干/祖细胞凋亡来保护小鼠免受辐射引起的肠损伤
DOI：
10.3390/nu13092910
复制
发表时间：
2021-08-24
期刊：
影响因子：
5.9
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Li W;Lin Y;Luo Y;Wang Y;Lu Y;Li Y;Guo H
寻找新的潜在靶点预防或缓解肿瘤临床放射治疗中的胃肠道综合征是当务之急。通过维生素D受体（VDR）介导的维生素D已被确定为对抗电离辐射（IR）诱导的损伤的保护性营养素。本研究旨在探讨维生素D受体（VDR）是否能抑制IR诱导的肠损伤，并探讨其可能机制。我们首次发现维生素D在体外诱导VDR表达并抑制IR诱导的DNA损伤和凋亡。VDR在肠隐窝中高度表达，并且在生理条件下对隐窝干/祖细胞增殖至关重要。接下来，暴露于IR的VDR缺陷小鼠显著增加了DNA损伤和隐窝干/祖细胞凋亡，导致肠再生受损以及存活时间缩短。此外，VDR缺陷激活Pmaip 1介导的IR处理小鼠肠隐窝干/祖细胞的凋亡途径，而通过siRNA转染抑制Pmaip 1表达保护IR诱导的细胞凋亡。因此，VDR通过Pmaip 1介导的途径抑制隐窝干/祖细胞凋亡来保护IR诱导的肠损伤。本研究结果揭示了VDR水平在临床放射治疗中的重要性，靶向VDR可能是治疗胃肠道综合征的有效策略。
It is urgent to seek new potential targets for the prevention or relief of gastrointestinal syndrome in clinical radiation therapy for cancers. Vitamin D, mediated through the vitamin D receptor (VDR), has been identified as a protective nutrient against ionizing radiation (IR)-induced damage. This study investigated whether VDR could inhibit IR-induced intestinal injury and explored underlying mechanism. We first found that vitamin D induced VDR expression and inhibited IR-induced DNA damage and apoptosis in vitro. VDR was highly expressed in intestinal crypts and was critical for crypt stem/progenitor cell proliferation under physiological conditions. Next, VDR-deficient mice exposed to IR significantly increased DNA damage and crypt stem/progenitor cell apoptosis, leading to impaired intestinal regeneration as well as shorter survival time. Furthermore, VDR deficiency activated the Pmaip1-mediated apoptotic pathway of intestinal crypt stem/progenitor cells in IR-treated mice, whereas inhibition of Pmaip1 expression by siRNA transfection protected against IR-induced cell apoptosis. Therefore, VDR protects against IR-induced intestinal injury through inhibition of crypt stem/progenitor cell apoptosis via the Pmaip1-mediated pathway. Our results reveal the importance of VDR level in clinical radiation therapy, and targeting VDR may be a useful strategy for treatment of gastrointestinal syndrome.