Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes
Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes
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在糖尿病中，宫内高血糖通过上调血清/糖皮质激素调节激酶1（SGK1）损害子宫内膜容受性。
DOI：
10.1007/s11427-021-2035-2
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发表时间：
2022-03-07
影响因子：
9.1
通讯作者：
Huang，Hefeng
中科院分区：
文献类型：
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作者：
Xu，Haiyan;Li，Jingyi;Huang，Hefeng
糖尿病是一种复杂的代谢紊乱，会对生殖功能产生不利影响。研究发现 SGK1 在糖尿病患者的多个组织中表达上调。然而，糖尿病对子宫内膜SGK1表达和子宫内膜容受性的影响仍不清楚。在本研究中，我们建立了链脲佐菌素诱导的糖尿病小鼠模型，观察到子宫内膜上皮着床部位减少、胞饮足发育迟缓、SGK1 增加以及 LIF 和 MUC1 表达异常。我们向正常小鼠的子宫腔注射高葡萄糖溶液，并在高葡萄糖培养基中培养子宫内膜细胞以模拟宫内高血糖。这两项研究都提供了令人信服的证据，表明高血糖可能导致胚胎植入减少以及 SGK1、LIF 和 MUC1 失调。此外，通过体内和体外SGK1的过表达，我们发现增强的SGK1还会降低LIF表达、增加MUC1表达并降低胚胎着床率。我们进一步确定高血糖激活的 SMAD2/3 可能负责 SGK1 的增强，并直接验证了 SMAD3 与 SGK1 启动子内相应 SMAD 结合元件之间的相互作用。综上所述，我们的研究证实了糖尿病相关的高血糖与子宫内膜容受性缺陷之间的关联。高血糖诱导的 SGK1 在这一病理过程中发挥着巨大作用，使其成为糖尿病相关生殖疾病的一个有吸引力的治疗靶点。
Diabetes is a complex metabolic disorder which can adversely affect reproductive function. SGK1 is found to be up-regulated in multiple tissues of diabetic patients. However, the effects of diabetes on endometrial SGK1 expression and endometrial receptivity remain unknown. In this study, we established a streptozotocin-induced diabetic mouse model and observed reduced implantation sites, retarded development of pinopodes, increased SGK1, and aberrant expression of LIF and MUC1 in the endometrial epithelium. We injected the uterine lumen of normal mice with high-glucose solution and cultured endometrial cells in high-glucose medium to mimic intrauterine hyperglycemia. Both studies provided compelling evidence that hyperglycemia could lead to diminished embryo implantation and dysregulated SGK1, LIF and MUC1. Additionally, through over-expression of SGK1in vivoandin vitro, we found that enhanced SGK1 also decreased LIF expression, increased MUC1 expression, and attenuated embryo implantation rate. We further identified that hyperglycemia-activated SMAD2/3 might be responsible for the enhancement of SGK1 and verified directly the interaction between SMAD3 and corresponding SMAD binding elements withinSGK1promoter. Taken together, our study confirmed the association between diabetes-related hyperglycemia and endometrial receptivity defects. Hyperglycemia-induced SGK1 has a tremendous role in this pathological process, rendering it as an attractive therapeutic target for diabetes-related reproductive disorders.