Activation of Nrf2 Pathway by Dimethyl Fumarate Attenuates Renal Ischemia-Reperfusion Injury

Abstract

Background: Dimethyl fumarate (DMF) is a novel antioxidant that selectively reduces hydroxyl radicals. This study aimed to investigate the potential role of DMF in the pathogenesis of renal ischemia-reperfusion injury (IRI) and the mechanisms involved.

Methods: C57BL/6 wild-type mice were treated with DMF or a vehicle. Subsequently, renal IRI was induced in mice by a model of right kidney nephrectomy and left renal ischemia for 30 minutes followed by reperfusion for 24 hours. Sham operation and phosphate-buffered saline were used as controls. Serum and renal tissues were collected at 24 hours after IRI to evaluate the influence of DMF on the recovery of renal function after IRI. Blood urea nitrogen and serum creatinine levels were measured. Kidney cell apoptosis was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling-positive staining. Interleukin 6 and tumor necrosis factor α cytokines in the kidney tissues were measured. Indicators of oxidative stress in the kidneys were detected. Finally, Nrf2-deficient mice were used to determine the protective role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) signaling pathways induced by DMF using western blot assay.

Results: DMF significantly attenuated renal dysfunction in mice and showed reductions in the severity of renal tubular injury, cell necrosis, and apoptosis. Moreover, DMF significantly reduced the amount of key inflammatory mediators. Additionally, DMF attenuated the malondialdehyde levels 24 hours after IRI but upregulated the superoxide dismutase activities. Western blot assay showed that DMF significantly increased the protein levels of Nrf2, HO-1, and NQO-1. Importantly, these DMF-mediated beneficial effects were not observed in Nrf2-deficient mice.

Conclusions: DMF attenuates renal IRI by reducing inflammation and upregulating the antioxidant capacity, which may be through Nrf2/HO-1and NQO1 signaling pathway.