Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.
Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Since Medical Foundation, Hualien, 970, Taiwan.
Free Radic Biol Med. 2021 Sep;173:70-80. doi: 10.1016/j.freeradbiomed.2021.07.026. Epub 2021 Jul 21.
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.
越来越多的研究表明间充质干细胞对多种疾病具有保护作用。然而，它们的一个关键限制是在应激条件下（包括糖尿病引起的高血糖）存活率降低。糖尿病引起的肾脏损伤涉及的分子机制尚未完全阐明。在本研究中，我们发现高葡萄糖（HG）降低了人近端肾小管上皮细胞的活力。此外，高血糖通过激活丝裂原活化蛋白激酶（MAPKs），包括 c-Jun N 末端激酶 JNK 和 p38 激酶，诱导氧化应激介导的细胞凋亡和纤维化。热休克蛋白 70 相互作用蛋白（CHIP）的羧基末端过表达在 HG 应激下显著挽救了细胞活力。此外，Western blot 分析、流式细胞术和 MitoSOX 染色显示，过表达 CHIP 的牙髓来源间充质干细胞（WJMSCs）减轻了高血糖诱导的线粒体氧化应激产生和细胞凋亡。与表达 CHIP 的 WJMSCs 共培养可维持 HK-2 细胞活力，并通过抑制 HG 诱导的 ROS 介导的 MAPK 激活来抑制细胞凋亡和纤维化。过表达 CHIP 的 WJMSCs 还挽救了链脲佐菌素诱导的糖尿病大鼠体重减轻和高血糖引起的肾脏损伤。综上所述，本研究结果表明 CHIP 抑制高血糖诱导的氧化应激，并赋予 MAPK 诱导的细胞凋亡和纤维化抵抗能力，提示 CHIP 保护 WJMSCs，高质量的 WJMSCs 对糖尿病引起的肾脏损伤具有治疗作用。
