Shanghai Key Laboratory of Embryo Original Diseases, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Reproduction. 2021 May 5;161(6):623-632. doi: 10.1530/REP-20-0677.
Preeclampsia is a gestational hypertensive disease; however, preeclampsia remains poorly understood. Bioinformatics analysis was applied to find novel genes involved in the pathogenesis of preeclampsia and identified CLDN1 as one of the most differentially expressed genes when comparing patients with preeclampsia and healthy controls. The results of the qRT-PCR, Western blotting and immunohistochemistry experiments demonstrated that CLDN1 was significantly downregulated in the chorionic villi in samples from patients with preeclampsia. Furthermore, knockdown of CLDN1 in HTR-8/SVneo cells resulted in the inhibition of proliferation and induction of apoptosis, and overexpression of CLDN1 reversed these effects. In addition, RNA-seq assays demonstrated that the gene BIRC3 is potentially downstream of CLDN1 and is involved in the regulation of apoptosis. Knockdown of CLDN1 confirmed that the expression level of BIRC3 was obviously decreased and was associated with a significant increase in cleaved PARP. Interestingly, the apoptotic effect in CLDN1 knockdown cells was rescued after BIRC3 overexpression. Overall, these results indicate that a decrease in CLDN1 inhibits BIRC3 expression and increases cleaved PARP levels thus participating in the pathogenesis of preeclampsia.
子痫前期是一种妊娠期高血压疾病；然而，子痫前期的发病机制仍知之甚少。本研究应用生物信息学分析方法寻找参与子痫前期发病机制的新基因，并在比较子痫前期患者和健康对照者时发现 CLDN1 是差异表达最显著的基因之一。qRT-PCR、Western blot 和免疫组织化学实验的结果表明，子痫前期患者的绒毛组织中 CLDN1 表达显著下调。此外，在 HTR-8/SVneo 细胞中敲低 CLDN1 会抑制细胞增殖并诱导细胞凋亡，而过表达 CLDN1 则逆转了这些效应。此外，RNA-seq 检测表明，基因 BIRC3 可能是 CLDN1 的下游基因，参与细胞凋亡的调控。CLDN1 敲低证实 BIRC3 的表达水平明显降低，与 cleaved PARP 水平的显著增加有关。有趣的是，在过表达 BIRC3 后，CLDN1 敲低细胞中的凋亡作用得到挽救。综上所述，这些结果表明 CLDN1 的减少抑制了 BIRC3 的表达，增加了 cleaved PARP 的水平，从而参与了子痫前期的发病机制。
