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Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes

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Abstract

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 SGK1 in vivo and in 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 within SGK1 promoter. 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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81490742, 82001537), the Fundamental Research Funds for the Central Universities (2021FZZX003-02-18) and the National Key Research and Development Program of China (2018YFC1004402). We thank Prof. Jun Zhou who works in Zhejiang University School of Medicine for expert technical assistance.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Reproductive Medicine Center, Ningbo First Hospital, Ningbo, 315100, China

    Haiyan Xu

  2. Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China

    Haiyan Xu, Jingyi Li, Luyang Jin, Dan Zhang, Bin Chen, Yiting Huang, Zhanghong Ke, Juan Liu, Jianzhong Sheng & Hefeng Huang

  3. Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Jingyi Li, Dan Zhang, Juan Liu & Hefeng Huang

  4. Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Jianzhong Sheng

  5. Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China

    Xinmei Liu, Xianhua Lin, Lin Gao & Hefeng Huang

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  1. Haiyan Xu
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Correspondence to Jianzhong Sheng or Hefeng Huang.

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Xu, H., Li, J., Jin, L. et al. Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes. Sci. China Life Sci. 65, 1578–1589 (2022). https://doi.org/10.1007/s11427-021-2035-2

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