Quercetin Ameliorates Diabetic Kidney Injury by Inhibiting Ferroptosis via Activating Nrf2/HO-1 Signaling Pathway

Abstract

Diabetic nephropathy (DN) is thought to be the major cause of end-stage renal disease. Due to its complicated pathogenesis and the low efficacy of DN treatment, a deep understanding of new etiological factors may be useful. Ferroptosis, a nonapoptotic form of cell death, is characterized by the accumulation of iron-dependent lipid peroxides to lethal levels. Ferroptosis-triggered renal tubular injury is reported to participate in the development of DN, and blocking ferroptosis might be an effective strategy to prevent the development of DN. Quercetin (QCT), a natural flavonoid that is present in a variety of fruits and vegetables, has been reported to ameliorate DN. However, its underlying nephroprotective mechanism is unclear. Herein, we explored the antiferroptosic effect of QCT and verified its nephroprotective effect using DN mice and high glucose (HG)-incubated renal tubular epithelial cell models. We found HG-induced abnormal activation of ferroptosis of renal tubular epithelial cells, and QCT treatment inhibited ferroptosis by downregulating the expression of transferrin receptor 1 (TFR-1) and upregulating the expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH-1), and the cystine/glutamate reverse antiporter solute carrier family 7 member (SLC7A11) in DN mice and HG-incubated HK-2 cells. Subsequently, both in vitro and in vivo results confirmed that QCT activated the NFE2-related factor 2 (Nrf2)/Heme oxygenase-1(HO-1) signaling pathway by increasing the levels of Nrf2 and HO-1. Therefore, this study supports that QCT inhibits the ferroptosis of renal tubular epithelial cells by regulating the Nrf2/HO-1 signaling pathway, providing a novel insight into the protective mechanism of QCT in DN treatment.

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis—A Systematic Review

“…It is defined by the body’s incapacity to regulate normal blood sugar levels, stemming from either insulin resistance or insufficient insulin production. Additionally, diabetes can contribute to the development of other conditions, such as diabetic nephropathy, cardiomyopathy, and neuropathies [ 77 , 78 , 79 ]. Interestingly, polyphenols quercetin, rhein, and glabridin have been shown to attenuate diabetic nephropathy through inhibition of ferroptosis.…”

“…Interestingly, polyphenols quercetin, rhein, and glabridin have been shown to attenuate diabetic nephropathy through inhibition of ferroptosis. Quercetin acted through the activation of the Nrf2/HO-1 pathway, rhein acted via the Rac1/NOX1/β-catenin pathway, while glabridin acted on the VEGF/Act/Erk pathway [ 78 , 80 , 81 ]. Furthermore, curcumin showed the ability to ameliorate diabetic cardiomyopathy by inhibiting ferroptosis.…”

An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory

“…In the majority of studies exploring diabetes and its chronic complications, a hyperglycemic exposure period of 48–72 h is typically considered representative of chronic hyperglycemia with long-term deleterious effects. This holds true for conditions such as DKD, DF, and diabetic cardiomyopathy (Hu et al 2024 ; Wang et al 2024 ; Li, et al 2024 ; Song et al 2023 ; Feng et al 2023 ). However, it is worth noting that the duration of exposure to high glucose, as well as the periods of exposure to normal glucose, vary significantly across studies examining metabolic memory.…”

Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy

“…A few plant extracts, like as Vitexin, are significant bioactive flavonoid monomers that demonstrate their anti-ferroptosis functions via stimulating GPX4 signaling [ 66 ]. In renal tubular epithelial cells, quercetin (QCT), a naturally occurring flavonoid derived from fruits and vegetables, increased the Nrf2/Heme oxygenase-1(HO-1) signaling to anti-ferroptosis [ 67 ]. Furthermore, some organic compounds have also demonstrated anti-ferroptosis properties.…”