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.

Zinc Depletion by TPEN Induces Apoptosis in Human Acute Promyelocytic NB4 Cells

“…Zinc is vital for numerous cellular processes, including survival, proliferation, aging, apoptosis, autophagy, and differentiation, both in normal and cancer cells [13-16]. As a cofactor for an estimated 3,000 human proteins [17], aberrations in zinc homeostasis contribute to development and progression of human cancers [18, 19].…”

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

“…13 If the damage is excessive or DNA repair is ineffective, then activation of cell death is the normal physiological response. 12 Although TPEN has been found to inhibit proliferation and induce apoptosis in many cell systems including lymphocytes, 14 epithelial cells, 15 hepatocytes, 16 breast cancer, 17 HT-29 colorectal cancer, 18,19 splenocytes, ovarian cancer, prostate cancer, 20 and pancreatic cancer, 21 its DNA damage potential and mechanisms remain unclear. We have previously shown that the generation of ROS and the redox cycling of copper following TPEN treatment result in targeted cell death of HCT116 human colon cancer cells.…”

High Glucose Enhances oxLDL-Induced Apoptosis in Human Renal Proximal Tubular Epithelial Cells Largely via Inducing Lectin-Like ox-LDL Receptor-1

“…High blood glucose is characteristic of DN [3] . Recent studies have suggested that LOX-1, the primary receptor for binding/uptake of ox-LDL [4] , plays an important role of in the pathogenesis and progression of DN [1,[6][7][8] .…”

“…Our study provides the first evidence that high glucose induces LOX-1 and hence enhances oxLDL-induced apoptosis in renal tubular epithelial cells, a key element in the pathogenesis and progression of DN [10,22] . We used primary HRPTEpCs as a cell model in this study, because: (1) tubular dysfunction plays a pivotal role in the development of DN [2] ; (2) high glucose-induced renal proximal tubular epithelial cell apoptosis reportedly serves as a significant factor causing renal functional and pathological changes from DN [2,3] . Compared with the normal control, high glucose concentration-dependently increased the expression of LOX-1 at both the mRNA and the protein levels, which led to increased ox-LDL binding by the cells.…”

“…Tubular dysfunction has been reported in patients with diabetes mellitus in the absence of microalbuminuria, suggesting a pivotal role of tubulo-interstitium in the development of DN [2] . Hyperglycemia is characteristic of DN, inducing renal tubular cell apoptosis by eliciting oxidative stress and inflammation [3] . Previous evidence indicated that in diabetic animal models and diabetic patients, chronic exposure to elevated blood glucose levels induces renal proximal tubular epithelial cell apoptosis, which serves as a significant factor causing renal functional and pathological changes from DN [2,3] .…”