title: Zinc modulates high glucose-induced apoptosis by suppressing oxidative stress in renal tubular epithelial cells.
abstract: Hyperglycemia is a characteristic of diabetic nephropathy, inducing renal tubular cell apoptosis by eliciting oxidative stress and inflammation. Zinc (Zn) is known as an essential trace element in many enzymes and proteins involved in antioxidant defenses, electron transport, and exerting antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of Zn on high glucose-induced cytotoxicity were explored using cultured renal tubular epithelial cells (NRK-52E). The authors discovered that Zn supplementation inhibited high glucose (HG)-induced NRK-52E cell apoptosis by attenuating reactive oxygen species production, inhibiting HG-induced caspase-3 and caspase-9 activation, and inhibiting the release of cytochrome c from mitochondria to the cytosol. Further analysis revealed that Zn supplementation facilitated cell survival through increasing nuclear translocation of NF-E2-related factor 2 (Nrf2), leading to increased regulation of levels of two antioxidant enzymes, hemeoxygenase-1 and glutamate cysteine ligase, which provided an adaptive survival response against the HG-induced oxidative cytotoxicity. Moreover, the Zn-mediated increases in Nrf2 activity were suppressed by the pharmacological inhibition of Akt or extracellular signal-regulated kinase 1/2. Taken together, these findings suggest that Zn antiapoptosis capacity through the activation of Akt and ERK signal pathways leads to Nrf2 activation and, subsequently, Nrf2 target gene induction, thereby protecting the NRK-52E cells from HG-induced apoptosis.
authors.affiliation: Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang, Liaoning, People's Republic of China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Chu
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Li
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Chi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D015032:Zinc / Q000494:pharmacology*
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D005947:Glucose; D015032:Zinc