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Activation of MST1 protects filtration barrier integrity of diabetic kidney disease in mice through restoring the tight junctions of glomerular endothelial cells

Acta Pharmacologica Sinica volume 46, pages 1345–1360 (2025)Cite this article

Abstract

As a pathological feature of diabetic kidney disease (DKD), dysregulated glomerular filtration barrier function could lead to the increased levels of proteinuria. The integrity of tight junctions (TJs) of glomerular endothelial cells (GECs) is a guarantee of physiological function of glomerular filtration barrier. Mammalian sterile 20-like kinase (MST1) is a key regulatory protein in the blood-brain barrier (BBB), and it regulates the expression of TJs-related proteins in cerebral vascular endothelial cells. Our previous study showed that MST1 was involved in renal tubulointerstitial fibrosis of DKD. In the present study we investigated the role of MST1 in barrier function of GECs of DKD, and explored its regulatory mechanisms. In kidney tissue section of DKD patients and db/db mice, and high glucose (HG)-cultured mouse glomerular endothelial cells (mGECs), we showed that MST1 was inactivated in the GECs of DKD accompanied by disrupted glomerular endothelial barrier. In db/db mice and HG-cultured mGECs, knockdown of MST1 increased proteinuria levels, and disrupted glomerular endothelial barrier through decreasing TJs-related proteins, whereas MST1 overexpression restored glomerular endothelial barrier through regaining TJs-related proteins. In db/db mice and HG-cultured mGECs, we demonstrated that MST1 inhibition induced TJs’s disruption of GECs via activating YAP1/TEAD signaling. Verteporfin (an inhibitor of YAP1-TEAD interaction) and PY-60 (a YAP1 agonist) were used to verify the role of YAP1/TEAD signaling in the regulation effect of MST1 on barrier function of mGECs. In conclusion, MST1 activation recovers glomerular endothelial barrier of DKD by regaining TJs-related proteins via inhibiting YAP1/TEAD signaling. This study highlights the multiple regulation of MST1 activation on kidney injury.

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Fig. 1: MST1 activation was significantly decreased in the GECs of humans with DKD and db/db mice.
Fig. 2: Phosphorylated MST1 was significantly decreased in HG-cultured mGECs.
Fig. 3: Effect of MST1 knockdown on the glomerular endothelial barrier of normal mice and NG-cultured mGECs.
Fig. 4: Effect of MST1 overexpression on the glomerular endothelial barrier in vivo and in vitro.
Fig. 5: Effect of HG on YAP1/TEAD signaling pathway in vitro.
Fig. 6: Effects of MST1 on YAP1/TEAD signaling pathway in mGECs.
Fig. 7: MST1 regulated glomerular endothelial barrier via YAP1/TEAD signaling pathway in mGECs.
Fig. 8: Target and molecular mechanism by MST1 in GECs improving filtration barrier integrity of DKD.

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Data availability

Data and materials are available upon request to the corresponding author.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China (82073906, 82104258, 82273987 and 82473983), the Natural Science Foundation of Jiangsu Province (BK20241957 and BK20241958), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the initializing Fund of Xuzhou Medical University (D2018011), and Postgraduate Research Practice Innovation Program of Jiangsu Province (KYCX23-2967 and KYCX24-3118). We sincerely thank Dr. Fu-xing Dong from the Public Experimental Research Center in Xuzhou Medical University for his enthusiastic help in the experiment of laser scanning confocal microscopy.

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  1. These authors contributed equally: Ting-ting Yang, Ying Liu, Yu-ting Shao

  2. These authors jointly supervised this work: Jun-jie Liu, Qian Lu, Xiao-xing Yin

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China

    Ting-ting Yang, Ying Liu, Yu-ting Shao, Dan-dan Pan, Si-tong Qian, Meng Yan, Xia Zhu, Qian Lu & Xiao-xing Yin

  2. Department of Pharmacy, Yuncheng Central Hospital affiliated to Shanxi Medical University, Yuncheng, 044000, China

    Lin Li

  3. Department of Pharmacy, The affiliated hospital of Xuzhou Medical University, Xuzhou, 221006, China

    Tao Wang

  4. New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China

    Zhen-zhou Jiang

  5. College of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China

    Bao-jing Li

  6. Department of Pharmacy, JingJiang People’s Hospital, Jingjiang, 214500, China

    Cai Heng

  7. The First Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, China

    Jun-jie Liu

  8. Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China

    Jun-jie Liu

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Contributions

The pre-clinical experiments of this work were designed by XXY, QL and TTY, and were performed by YL, LL and YTS. The clinical experiments were designed by JJL and TW, and were performed by YL. YL, LL, YTS and DDP analyzed the data, edited of the figures and tables. MY and CH supplied reagent or helped in treatments to animals and cells. BJL, XZ, ZZJ and STQ helped with article structural configuration. TTY, YL and YTS wrote the manuscript. TTY, XXY, JJL and QL reviewed the manuscript.

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Correspondence to Jun-jie Liu, Qian Lu or Xiao-xing Yin.

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All animal investigations were approved by the Laboratory Animal Ethics Committee of Xuzhou Medical University and adhered to ethical standards outlined in Guide for Care and Use of Laboratory Animals from National Institutes of Health.

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Yang, Tt., Liu, Y., Shao, Yt. et al. Activation of MST1 protects filtration barrier integrity of diabetic kidney disease in mice through restoring the tight junctions of glomerular endothelial cells. Acta Pharmacol Sin 46, 1345–1360 (2025). https://doi.org/10.1038/s41401-024-01421-6

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