CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells attenuate hyperglycemia-induced oxidative stress-mediated kidney injuries in diabetic rats

Ayaz Ali; Marthandam Asokan Shibu; Chia-Hua Kuo; Jeng-Feng Lo; Ray-Jade Chen; Cecilia Hsuan Day; Tsung-Jung Ho; Vijaya PadmaViswanadha; Wei-Wen Kuo; Chih-Yang Huang

doi:10.1016/j.freeradbiomed.2021.07.026

CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells attenuate hyperglycemia-induced oxidative stress-mediated kidney injuries in diabetic rats

Free Radic Biol Med. 2021 Sep:173:70-80. doi: 10.1016/j.freeradbiomed.2021.07.026. Epub 2021 Jul 21.

Authors

Affiliations

¹ Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.
² Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Since Medical Foundation, Hualien, 970, Taiwan.
³ Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan.
⁴ Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
⁵ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
⁶ Department of Nursing, MeiHo University, Pingtung, 91202, Taiwan.
⁷ Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan; Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
⁸ Department of Biotechnology, Bharathiar University, Coimbatore, 641 046, India.
⁹ Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan; Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, 406, Taiwan.
¹⁰ Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Since Medical Foundation, Hualien, 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan. Electronic address: cyhuang@mail.cmu.edu.tw.

PMID: 34298092
DOI: 10.1016/j.freeradbiomed.2021.07.026

Abstract

Accumulating studies have demonstrated the protective roles of mesenchymal stem cells against several disorders. However, one of their crucial limitations is reduced viability under stress conditions, including the hyperglycemia induced by diabetes. The molecular mechanisms involved in diabetes-induced kidney injuries are not fully elucidated. In this study, we found that high glucose (HG) reduced human proximal tubular epithelial cell viability. Further, hyperglycemia induced oxidative stress-mediated apoptosis and fibrosis in HK-2 cells via activation of the mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal kinase JNK and p38 kinase. Carboxyl terminus of HSP70 interacting protein (CHIP) overactivation considerably rescued cell viability under HG stress. Moreover, Western blot analysis, flow cytometry, and MitoSOX staining revealed that hyperglycemia-induced mitochondrial oxidative stress production and apoptosis were attenuated in CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Co-culture with CHIP-expressing WJMSCs maintained HK-2 cell viability, and inhibited apoptosis and fibrosis by attenuating HG-induced ROS-mediated MAPK activation. CHIP-overexpressing WJMSCs also rescued the decreased kidney weight and hyperglycemia-induced kidney damage observed in streptozotocin-induced diabetic rats. Cumulatively, the current research findings demonstrate that CHIP suppresses hyperglycemia-induced oxidative stress and confers resistance to MAPK-induced apoptosis and fibrosis, and suggests that CHIP protects WJMSCs and the high quality WJMSCs have therapeutic effects against diabetes-induced kidney injuries.

Keywords: Apoptosis; Carboxyl terminus of HSP70 interacting protein; Diabetes; Fibrosis; Rats; Wharton's jelly derived mesenchymal stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental* / complications
Diabetes Mellitus, Experimental* / metabolism
Hyperglycemia* / metabolism
Kidney / metabolism
Mesenchymal Stem Cells*
Oxidative Stress
Rats
Wharton Jelly*