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

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. 2024 Dec 6. doi: 10.1038/s41401-024-01421-6.
Ting-Ting Yang # 1,  Ying Liu # 1,  Yu-Ting Shao # 1,  Lin Li 2,  Dan-Dan Pan 1,  Tao Wang 3,  Zhen-Zhou Jiang 4,  Bao-Jing Li 5,  Si-Tong Qian 1,  Meng Yan 1,  Xia Zhu 1,  Cai Heng 6,  Jun-Jie Liu 7 8,  Qian Lu 9,  Xiao-Xing Yin 10
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.
  • 2 Department of Pharmacy, Yuncheng Central Hospital affiliated to Shanxi Medical University, Yuncheng, 044000, China.
  • 3 Department of Pharmacy, The affiliated hospital of Xuzhou Medical University, Xuzhou, 221006, China.
  • 4 New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
  • 5 College of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
  • 6 Department of Pharmacy, JingJiang People's Hospital, Jingjiang, 214500, China.
  • 7 The First Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, China. 315428099@qq.com.
  • 8 Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China. 315428099@qq.com.
  • 9 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. luqian@xzhmu.edu.cn.
  • 10 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. yinxx@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 39643641 DOI: 10.1038/s41401-024-01421-6
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.

Keywords

MST1; diabetic kidney disease; endothelial barrier function; glomerular endothelial cells; proteinuria; tight junctions.

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