Nrf2 participates in the anti-apoptotic role of zinc in Type 2 diabetic nephropathy through Wnt/β-catenin signaling pathway

Zinc (Zn), as an essential trace element, has been approved to serve many roles in diabetic studies. Also Zn deficiency will aggravate renal damage in diabetes through suppression of nuclear factor-erythroid 2-related factor 2 (Nrf2) expression and function. The purpose of this study was to illustrate the role of Zn in renal apoptosis in diabetes and whether Nrf2 participated in the process. Type 2 diabetes mice model was induced by a single dose of streptozotocin (STZ) injection after high-fat diet (HFD) feeding for 3 months, then the mice were given diets supplemented with different concentrations of Zn (control, 30 ppm; low-concentration, 0.85 ppm). After 12-week treatment, morphology and associated protein expressions were examined. The results showed that low Zn diet significantly aggravated the level of renal apoptosis during diabetes, performed as the upregulation of caspase-3 expression. In addition, either low Zn diet or diabetes or both dramatically decreased the expression of Nrf2 and P-AKT in kidney. Moreover, the expression of β-catenin in kidney was increased markedly in diabetic groups. Mechanistic study applying human renal tubular epithelial cells (HK11) confirmed the role of Nrf2, as silencing Nrf2 expression abolished Zn supplementation protection against high sugar + high fat + low Zn-induced apoptosis and downregulation of β-catenin expression. All these results suggest that Nrf2 plays a key role in Zn protection against Type 2 diabetes induced renal apoptosis, which might be through Wnt/β-catenin signaling pathway.