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Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models

Author

Listed:
  • Ke Song

    (Southern Medical University)

  • Xinyan Yang

    (Southern Medical University)

  • Geng An

    (Reproductive Medicine Center of The Third Affiliated Hospital of Guangzhou Medical University)

  • Xinyu Xia

    (Southern Medical University)

  • Jiexiang Zhao

    (Southern Medical University)

  • Xiaoheng Xu

    (Southern Medical University)

  • Cong Wan

    (Southern Medical University)

  • Tianyuan Liu

    (Southern Medical University)

  • Yi Zheng

    (Southern Medical University)

  • Shaofang Ren

    (Southern Medical University)

  • Mei Wang

    (Southern Medical University)

  • Gang Chang

    (Shenzhen University Health Science Center)

  • Shane J. F. Cronin

    (IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences)

  • Josef M. Penninger

    (IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
    University of British Columbia)

  • Tao Jing

    (Reproductive Medicine Center, Guangdong Second Provincial General Hospital)

  • Xianghong Ou

    (Reproductive Medicine Center, Guangdong Second Provincial General Hospital)

  • Shuan Rao

    (Southern Medical University)

  • Zhaoting Liu

    (Southern Medical University)

  • Xiao-Yang Zhao

    (Southern Medical University
    Southern Medical University
    National Clinical Research Center for Kidney Disease
    Southern Medical University)

Abstract

Type 2 diabetes mellitus is one of the most prevalent metabolic diseases presenting with systemic pathologies, including reproductive disorders in male diabetic patients. However, the molecular mechanisms that contributing to spermatogenesis dysfunction in diabetic patients have not yet been fully elucidated. Here, we perform STRT-seq to examine the transcriptome of diabetic patients’ testes at single-cell resolution including all major cell types of the testis. Intriguingly, whereas spermatogenesis appears largely preserved, the gene expression profiles of Sertoli cells and the blood-testis barrier (BTB) structure are dramatically impaired. Among these deregulate pathways, the Apelin (APLN) peptide/Apelin-receptor (APJ) axis is hyper-activated in diabetic patients’ testes. Mechanistically, APLN is produced locally by Sertoli cells upon high glucose treatment, which subsequently suppress the production of carnitine and repress the expression of cell adhesion genes in Sertoli cells. Together, these effects culminate in BTB structural dysfunction. Finally, using the small molecule APLN receptor antagonist, ML221, we show that blocking APLN/APJ significantly ameliorate the BTB damage and, importantly, improve functional spermatogenesis in diabetic db/db mice. We also translate and validate these findings in cultured human testes. Our findings identify the APLN/APJ axis as a promising therapeutic target to improve reproduction capacity in male diabetic patients.

Suggested Citation

  • Ke Song & Xinyan Yang & Geng An & Xinyu Xia & Jiexiang Zhao & Xiaoheng Xu & Cong Wan & Tianyuan Liu & Yi Zheng & Shaofang Ren & Mei Wang & Gang Chang & Shane J. F. Cronin & Josef M. Penninger & Tao Ji, 2022. "Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34990-3
    DOI: 10.1038/s41467-022-34990-3
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