Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.058
Melatonin Protects Chronic Kidney Disease Mesenchymal Stem/Stromal Cells against Accumulation of Methylglyoxal via Modulation of Hexokinase-2 Expression
Gyeongyun Go1,2, Yeo Min Yoon3, Sungtae Yoon4, Gaeun Lee1,2, Ji Ho Lim1, Su-Yeon Han4 and Sang Hun Lee1,2,3,4,*
1Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31151,
2Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang University, Cheonan 31151,
3Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401,
4Stembio Ltd., Asan 31538, Republic of Korea
*E-mail: shlee0551@gmail.com
Tel: +82-2-709-9029, Fax: +82-2-792-5812
Received: March 29, 2021; Revised: May 8, 2021; Accepted: June 3, 2021; Published online: July 15, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Melatonin, Hexokinase, Methylglyoxal, Mesenchymal stem/stromal cells, Mitochondria, Glycolysis


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