Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition

Abstract

Increasing evidence from human and laboratory studies showed the effect of zinc (Zn) on diabetic complications. Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays important role in the prevention of oxidative damage. This study was to define whether Zn statues (deficiency or supplement) affect the Nrf2 expression and function, and also affect the damage severity of human renal tubular (HK11) cells exposed to high glucose (HG) with palmitate (Pal) and kidney of diabetic mice induced by multiple low-dose streptozotocins. For Zn deficiency diabetic mice were treated with Zn chelator PTEN at 5 mg/kg bw daily for 4 months. Results showed that HG/Pal significantly increased the expression of pro-fibrotic mediators, connective tissue growth factor and PAI-1, in HK11 cells, which was exacerbated by TPEN that depleted intracellular free Zn and decreased Nrf2 expression and transcription. Zn supplement prevented the effects of TPEN and also increased Akt and GSK-3β phosphorylation with a decrease in Nrf2 nuclear exporter, Fyn. All these effects of Zn were abolished by Akt inhibitor. Therefore, Zn up-regulates Nrf2 function via activating Akt-mediated inhibition of Fyn function. Treatment of diabetic mice with TPEN decreased renal Zn level and Nrf2 expression and transcription, with an exacerbation of renal oxidative damage, inflammation and fibrosis. These results suggest the essentiality of Zn for Nrf2 expression and transcription function.

Zinc Chloride Protects against Streptozotocin-Induced Diabetic Nephropathy in Rats

“…Consistent with our work, several studies showed the ability of Zinc Chloride to control hyperglycemia [10] [43]. In addition, our results showed a significant increase in the mean arterial blood pressure in the diabetic control rats.…”

“…Another study also showed the beneficial effects of Zinc Chloride in controlling hyperglycemia thus preserving liver architecture and ameliorating NO, MDA, superoxide dismutase (SOD) and GSH levels [10]. Our results, showing the antioxidant capacity of Zinc Chloride, are in accordance with Li et al, in 2014, who reported the role of Zinc Chloride in preventing renal oxidative damage via upregulation of nuclear factor-erythroid 2-related factor (Nrf2) [43].…”

Chromium (VI)-induced transformation is enhanced by Zn deficiency in BALB/c 3T3 cells

“…Zinc has also been recognized as an intracellular second messenger (Murakami and Hirano, 2008;Prasad, 2014). For example, zinc is a signal for immune cell (Kabu et al, 2006;Yamasaki et al, 2012) and is essential for the transcription function of Nrf2 in diabetic models (Li et al, 2014). It may be that the high susceptibility to Cr(VI)-induced transformation that results from zinc deficiency in cell culture is associated with the loss of these zinc functions.…”

Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters

“…Zinc dyshomeostasis is intimately related to such disorders as metabolic syndrome, diabetes, and diabetic complications. Zinc has been reported to induce Nrf2 in an animal model and therefore considered an activator of Nrf2 [60].…”