Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Melatonin Protects Chronic Kidney Disease Mesenchymal Stem/Stromal Cells against Accumulation of Methylglyoxal via Modulation of Hexokinase-2 Expression

  • Go, Gyeongyun (Department of Biochemistry, Soonchunhyang University College of Medicine) ;
  • Yoon, Yeo Min (Medical Science Research Institute, Soonchunhyang University Seoul Hospital) ;
  • Yoon, Sungtae (Stembio Ltd.) ;
  • Lee, Gaeun (Department of Biochemistry, Soonchunhyang University College of Medicine) ;
  • Lim, Ji Ho (Department of Biochemistry, Soonchunhyang University College of Medicine) ;
  • Han, Su-Yeon (Stembio Ltd.) ;
  • Lee, Sang Hun (Department of Biochemistry, Soonchunhyang University College of Medicine)
  • Received : 2021.03.29
  • Accepted : 2021.06.03
  • Published : 2022.01.01
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Abstract

Treatment options for patients with chronic kidney disease (CKD) are currently limited; therefore, there has been significant interest in applying mesenchymal stem/stromal cell (MSC)-based therapy to treat CKD. However, MSCs harvested from CKD patients tend to show diminished viability and proliferation due to sustained exposure to uremic toxins in the CKD environment, which limits their utility for cell therapy. The application of melatonin has been demonstrated to improve the therapeutic efficacy of MSCs derived from and engrafted to tissues in patients suffering from CKD, although the underlying biological mechanism has not been elucidated. In this study, we observed overexpression of hexokinase-2 (HK2) in serum samples of CKD patients and MSCs harvested from an adenine-fed CKD mouse model (CKD-mMSCs). HK2 upregulation led to increased production levels of methylglyoxal (MG), a toxic metabolic intermediate of abnormal glycolytic processes. The overabundance of HK2 and MG was associated with impaired mitochondrial function and low cell proliferation in CKD-mMSCs. Melatonin treatment inhibited the increases in HK2 and MG levels, and further improved mitochondrial function, glycolytic metabolism, and cell proliferation. Our findings suggest that identifying and characterizing metabolic regulators such as HK2 in CKD may improve the efficacy of MSCs for treating CKD and other kidney disorders.

Keywords

Acknowledgement

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2019M3A9H1103495).

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