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

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 Jing, Xianghong Ou, Shuan Rao (), Zhaoting Liu () and Xiao-Yang Zhao ()
Additional contact information
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34990-3

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