Attenuation of Glomerular Injury in Diabetic Mice with Tert-Butylhydroquinone through Nuclear Factor Erythroid 2-Related Factor 2-Dependent Antioxidant Gene Activation

Abstract

Background/Aims: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a positive regulator of the expression of antioxidant genes. This study is aimed at examining the effect of tert-butylhydroquinone (tBHQ), an activator of Nrf2, on hyperglycemia-related diabetic nephropathy. Methods: CD-1 mice were induced with streptozotocin and treated with 1% tBHQ, or omitting it, in their diet for 12 weeks. Four and twelve weeks later, the levels of serum and glomerular malondialdehyde (MDA), blood glucose, kidney and body weights, and proteinuria were measured. The pathogenic process in the kidney was examined histologically and by transmission electron microscopy. The relative levels of Nrf2, heme oxygenase-1 (HO-1), γ-glutamylcysteine synthethase (γ-GCS) expression and nuclear accumulation of Nrf2 in the glomeruli were determined by reverse transcription polymerase chain reaction and Western blot assays. Results: In the glomeruli of diabetic mice, treatment with tBHQ significantly reduced the levels of serum and glomerular MDA, kidney weight and proteinuria, decreased fibronectin accumulation and mitigated the pathogenic processes. It also enhanced Nrf2, HO-1 and γ-GCS expression and Nrf2 nuclear accumulation. Conclusions: tBHQ has beneficial effects on reducing hyperglycemia-induced kidney injury, which is associated with the enhanced expression of Nrf2, and its downstream antioxidant HO-1 and γ-GCS in the glomeruli of diabetic mice.

Preventive effect of tert-butylhydroquinone on scrotal heat-induced damage in mouse testes

“…Several studies have explored the protective effect of tBHQ. Oral administration of tBHQ prevented glomerular injury in diabetic mice (Li et al, 2011). Moreover, pre-treatment with tBHQ also protected mice brains against traumatic brain injury-induced inflammatory damage (Jin et al, 2011).…”

Tertiary-Butylhydroquinone Upregulates Expression of ATP-Binding Cassette Transporter A1 via Nuclear Factor E2-Related Factor 2/Heme Oxygenase-1 Signaling in THP-1 Macrophage-Derived Foam Cells

“…26 Many studies have reported the important role of tBHQ as a dietary antioxidant in preventing oxidative damage caused by active oxygen radicals in living systems. [27][28][29] Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms, including oxidative stress and inflammation, which can be reduced by antioxidants. 30 Recent research suggests that a tBHQ diet increases the expression of LDL-related protein-1, a multi ligand endocytotic receptor involved in transporting amyloid-beta peptide out of the brain.…”

Dysregulation of Nrf2 Signaling in Diabetes: An Opportunity for a Multitarget Approach

“…Feeding diabetic mice a diet containing 1% tBHQ significantly reduced the levels of serum and glomerular malondialdehyde, kidney weight and proteinuria, as well as decreased levels of fibronectin while concomitantly increasing Nrf2 protein expression and nuclear accumulation and expression of HO-1 and γ-GCS [8].…”

“…The antioxidants sulforaphane (SFN) and tetrahydroxyquinone (tBHQ) disrupt the Keap1-Nrf2 complex and have been shown to be effective in reducing or preventing diabetic complications by increasing Nrf2 content and activity in animal models [8,11,44]. It was originally believed that SFN and tBHQ increased Nrf2 activity by modifying cysteine residues of the Nrf2-Keap1 complex and caused dissociation in a manner similar to ROS [32].…”

“…Nrf2 is decreased in diabetic mice and patients with type 2 diabetes mellitus (T2DM), which contributes to increased oxidative stress, endothelial dysfunction, insulin resistance, nephropathy, and increased cardiac insult [7][8][9]. Genetic overexpression of Nrf2 prevents the onset of T2DM in mice and small molecule activation of Nrf2 reduces oxidative stress, and a myriad of diabetic complications, including cardiovascular complications, nephropathy, and neuropathy [9][10][11].…”